Transcript Tocolytic drugs update

By
Dr.Asmaa Al sanjary
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Preterm delivery is defined by a birth occurring
before 37 completed weeks of gestation .
Prematurity is multifactorial and its incidence
has increased during the last decade in most
occidental countries, probably due to increased
risk factors responsible for elective prematurity.
The mechanisms for preterm labour are still
unclear. It could be associated either with a
premature activation of the physiological
contracting process or with a pathological factor
responsible for uterine contractions, leading to
preterm delivery .
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Tocolytic drugs have been available for
several decades but their actions are directed
toward the effects and not the causes of
preterm labour .
Tocolysis aims not only to inhibit uterine
contractions but also to allow a safe transfer
of the pregnant patient to a tertiary care
centre ,It gives the opportunity to
administrate corticosteroids for preventing
neonatal risks associated with prematurity
Their efficacy depend on an early and
accurate diagnosis of the condition; the fetal
fibronectin, and cervical length
ultrasonography.
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Drugs safety and side
effect profile is a major
concern not only for
the pregnant women
but also for the fetus.
administration route
and the optimal range
of gestational age for
these treatments
Are utilized as a tocolytic since the 1970s.
Ritodrine was the first tocolytic approved by the FDA
in 1980; it was voluntarily removed from the
market in 1993 due to concerns of serious
adverse effects.
Due to recent warnings from the FDA concerning the
lack of safety with the prolonged use of
terbutaline, its use as a preventative agent or use
beyond 48 to 72 hours is no longer recommended.
In addition, oral terbutaline is not recommended
as its effectiveness has not been established
Common adverse effects, when beta-agonists are
compared to no treatment or placebo, include
palpitation(68% with beta-agonists vs. 5% with controls),
Tremor (39% vs. 4%),
nausea (20% vs. 12%),
headache (23%vs. 6%)
and chest pain (10% vs. 1%).
Rare, but serious and potentially life threatening adverse
effects have been reported following beta-agonists use
and a few maternal deaths associated with the use of
these drugs were reported.
Pulmonary edema is a well-documented
Complication , usually associated with aggressive
Intravenous hydration. A systematic review
reported one case of pulmonary edema among 850
women (1/425 with beta-agonists vs. 0/427 with
placebo).
In conclusion, despite their efficiency, β 2
agonists’ safety profile is a real
concern responsible for therapy
discontinuation and choosing
alternative tocolytic drugs.
Other tocolytic drugs (magnesium sulphate,
indomethacin and atosiban),has fewer types of
adverse effects reported and these occurred
Less frequently.
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These agents are in competition with the
myometrial and decidual oxytocin
receptors. The only drug used in clinical
practice is atosiban. It blocks in
a reversive manner the
intracytoplasmic calcium release
associated with contractions and
downregulates prostaglandin
synthesis.
Atosiban is widely used
in clinical practice because
of its low side effects profile
and seems to be an adequate therapeutic choice
for Effective tocolysis with
a low maternal and fetal
adverse effects profile.
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Atosiban represents an advance in currently available
tocolytics, and should be considered a first-line tocolytic
for the management of SPTL.
Atosiban is licensed in Europe for treatment of SPTL.
The recommended dosage and administration schedule
for atosiban is a three-step procedure .
Duration of treatment should not exceed 48 h and the
total dose given during a full course should preferably
not exceed 330 mg of atosiban. In the early gestational
age with or without PPROM, the use of atosiban can be
prolonged for a further few days without any significant
side effects.
For atosiban, the only documented adverse effect
is nausea (11% with atosiban vs.5% with placebo)
but this is only of short duration and only in
association within about a minute during which
the bolus dose is administered.
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As magnesium is a calcium antagonist, it decreases
calcium intracellular concentration
no benefit of Magnesium sulphate administration over
placebo use in preterm labour .
As the drug is crossing the placenta, there were
concerns about fetal safety.
An increased risk of perinatal death and neonatal
neurological and metabolic adverse effects at high
dosage .
Higher risk of death but a non-significant reduction in
cerebral palsy at 18-months (corrected age) in infants
exposed to magnesium sulfate.
It can also affect maternal neuromuscular system.
Over a serum concentration of 9 mg/dL, there is a
high toxicity risk resulting in disappearance of
reflexes and respiratory depression and at 18mg/dl
there is risk of cardiac arrest.
Despite questionable safety and efficacy, still be
used by obstetrician as their primary tocolytic
therapy.
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There is no evidence any more to
recommend this drug as a first-line
tocolytic agent .
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Prostaglandin-synthase or cyclooxygenase
(COX) isoforms COX-1 and -2 are essential
enzymes for converting arachidonic acid to
prostaglandins.
Indomethacin, a nonspecific COX inhibitor, has
been reported in studies and in a recent metaanalysis to be an efficient tocolytic drug
compared to placebo, significantly delaying
preterm delivery .
It can be administrated rectally or orally.
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Its use should be restricted in duration as the drug use for 2
days will not cause oligohydraminos. It should be limited to
pregnancies below 32 weeks because of fetal ductus
arteriosus closure risk and decreased urine production
responsible for oligohydramnios . These treatments also
have maternal side effects including gastric ulcer or asthma
recurrence.
COX-2 inhibitors such as nimesulide or rofecoxib have been
studied in animal but not yet in humans and are not actually
recommended for preventing preterm labour in clinical
practice .
In conclusion, indomethacin is an efficient tocolytic
drug with no serious adverse drug reaction and is
indicated for short-term effect during the second
trimester of pregnancy.
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Calcium-Channel Blockers :These agents are
interfering with the calcium ions transfer
through the myometrial cell membrane. They
decrease intracellular free calcium
concentration and induce myometrial
relaxation .
Nifedipine is the most commonly used single
drug for preterm labour inhibition. nifedipine
compared with β adrenergic receptor agonists
has higher efficiency and a lower side effects .
Nifidipine is used at a daily dose of 30–60 mg daily.
An initial loading dose of 20 mg orally is
given orally, followed by 10–20 mg every 6–8
hours.
The sublingual form is not recommended for
treatment of preterm labor because it acts more
rapidly than the oral form and can cause acute
hypotension.
Nifidipine is commonly used in clinical practice
as they has being generally well-tolerated as a
single agent therapy.
Use with magnesium sulfate should be avoided
as it has resulted in harmful consequences
including cardiovascular collapse.
nifedipine is aN efficient tocolytic agent,
with an easy oral route of administration,
few side effects, and a low neonatal
complications rate. However, it should be
used with caution in patients with
compromised cardiovascular condition as
they may be at risk of pulmonary oedema
and cardiac failure
NO is a powerful vasodilator synthesized during
an amino acid oxidation process catalysed by NO
synthase. It is present in myometrial cells and
increases cGMP content by interaction with
guanylyl cyclase.
Transdermal nitroglycerin administration has been
used in preterm labour only in small series, It has
better tocolytic effect than placebo on delaying
delivery for two days(similar to ritodrine).
Major side effects are maternal headache and sever
hypotension.
There is risk of tocolysis failure
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there is no large randomized
studies available,
NO is not used in clinical routine.
Its use still exparmental.
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Some drugs are used as first-line single therapy
such as β adrenergic receptor agonists and
atosiban in Europe.while in America Atosiban
is not licensed for use as it’s believed not
reduce the incidence of preterm birth or
improve neonatal outcomes when compared to
placebo,with increase in fetal/infant death seen
in those exposed to atosiban.
severe cases, combined therapy could be
offered but should be restricted because of
adverse effects addition and no improvement
in perinatal outcome.
 The combination of magnesium sulphate
and nifedipine should be avoided because of
reported cases of symptomatic hypocalcemia,
Neuromuscular blockade, and cardiac toxicity,
including maternal death.
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calcium channel blockers, particularly nifedipine, are
used as a reasonable choice for initial tocolysis due
to the low incidence of adverse effects, oral route
of administration, efficacy in improving neonatal
outcomes, and potential for use at any gestational
age.
Indomethacin is an available alternative for
pregnancies of less than 32 weeks gestation as
Premature closure of the ductus arteriosus has
been shown to occur more often in those >32
weeks,
it should be avoided in patients at increased risk of
bleeding and those with renal or hepatic
insufficiency, gastrointestinal disease, or asthma.
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Specific conditions are subject to discussion: in
multiple pregnancies, expanded blood volume
and anaemia may predispose to pulmonary
oedema when tocolytic agents such as β
adrenergic receptor agonists,magnesium
sulphate, and calcium channel blockers are
prescribed. In these pregnancies, atosiban, with
its low side effects incidence, seems to be the
safest choice.
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Last generation of oxytocin receptor
antagonists such as barusiban could be more
efficient and have less affinity for the
vasopressin receptors .
Specific COX-2 inhibitors or “coxibs,”
prostaglandin receptors antagonists could be
promising tocolytic alternatives