TOCOLYSIS

Moderator :-
Dr.Lakshmikantha G.

Presenter:-
Dr. Mohan Kumar D
CONTENTS
Introduction
Pharmacology.
Indications for tocolysis.
Contraindications for tocolysis.
TOCOLYTICS
Calcium channel blockers.
Magnesium sulphate.
Atosiban.
Adrenergic agonists.
Indomethacin.
Introduction
The inhibition of myometrial contractions is called
tocolysis, and an agent administered to that end is
referred to as a tocolytic.

Because the contracting uterus is the most often

recognized antecedent of Pre term birth, stopping
contractions has been the focus of therapeutic
approaches.
Meta-analyses of studies of individual tocolytic drugs
report limited prolongation of pregnancy but no
decrease in PTB, and they rarely offer information
about whether prolongation of pregnancy was
accompanied by improved infant outcomes.
Delayed delivery for 48 hours to allow antenatal
transport and corticosteroids to reduce neonatal
morbidity and mortality are thus the main rationale
for use of these drugs.
PHARMACOLOGY
The key process in smooth muscle contraction, is
myosin light-chain phosphorylation. This reaction is
controlled by myosin lightchain kinase (MLCK).
The activity of tocolytic agents can be explained by
their effect on the factors that regulate the activity of
this enzyme, notably calcium and cyclic adenosine
monophosphate (cAMP).
Indications for Tocolysis
Tocolysis is considered for women with suspected
preterm labour who have had an otherwise
uncomplicated pregnancy.
External cephalic version.
Manual replacement of uterine inversion.
CONTRAINDICATIONS TO TOCOLYSIS
Common maternal contraindications to tocolysis
include
Preeclampsia or gestational hypertension,
with severe features.
Hemorrhage. And
Significant maternal cardiac disease.
Fetal contraindications to tocolysis include
Gestational age of greater than 37
weeks.
 Fetal demise or lethal anomaly.
 Chorioamnionitis, and
 Evidence of acute or chronic fetal
compromise.
 TOCOLYTICS
Calcium channel blockers:-
Nifedipine is the calcium channel blocker most
studied as a tocolytic agent; it more selectively inhibits
uterine contractions compared with other CCBs.
MOA :- Calcium channel blockers directly block the
influx of calcium ions through the cell membrane and
also inhibit release of intracellular calcium from the
sarcoplasmic reticulum.
The decrease in intracellular free calcium leads to
inhibition of calcium-dependent MLCK-mediated
phosphorylation and results in myometrial relaxation.
The Cochrane Collaboration meta-analyses support
calcium channel blockers as short-term tocolytics,
compared with other available agents, because of
relatively greater suppression of contractions and
fewer side effects than other agents.
Rates of birth within 7 days of treatment and before
34 weeks gestation were significantly reduced with
calcium channel blockers, as were the rates of
neonatal morbidities that included RDS ,NEC, IVH
and jaundice when compared with treatment with
other tocolytics.
SIDE EFFECTS OF CCBs
Maternal side effects:-
Dizziness.
Flushing.
Hypotension when used with magnesium sulfate.
Suppression of heart rate, contractility, and left
ventricular systolic pressure and
Neuromuscular blockade.
Concomitant or sequential use of
calcium channel blockers with β-
mimetics is not recommended, nor
is concurrent administration of
magnesium, owing to reports of
skeletal muscle blockade when
nifedipine was given with
magnesium sulfate.
Treatment protocol
The suggested dose of nifedipine is an initial dose
of 20mg followed by 10-20mg three to four times
daily, adjusted according to uterine activity for up
to 48hours.
The half-life of nifedipine is approximately 2 to 3
hours.
And the duration of action of a single orally
administered dose is up to 6 hours.
Plasma concentrations peak in 30 to 60 minutes.
Nifedipine is almost completely metabolized in the
liver and excreted by the kidney.
SUMMARY OF TREATMENT WITH CALCIUM
CHANNEL BLOCKERS

Nifedipine has been used increasingly as a tocolytic

because of its low incidence of significant maternal
and fetal side effects and ease of administration.
Nifedipine should not be combined with magnesium
or β-mimetics.
It should be avoided in the presence of intrauterine
infection, maternal hypertension, and cardiac disease.
MAGNESIUM SULPHATE
Magnesium sulfate acts as a tocolytic by competing
with Ca2+ ions for entry into myometrium through
both voltage sensitive as well as ligand gated Ca2+
channels.
 However, its use to delay premature labour is risky,
may increase perinatal mortality and is not
recommended now.
Maternal side effects
Flushing, diaphoresis, nausea, loss of deep-tendon
reflexes (serum levels of 9.6 to 12 mg/dL).
Respiratory paralysis (at serum levels of 12 to 18
mg/dL).
Cardiac arrest (at serum levels of 24 to 30 mg/dL).
When used with calcium channel blockers,
suppression of heart rate, contractility, and left
ventricular systolic pressure and neuromuscular
blockade.
ATOSIBAN
Atosiban is a peptide analogue of oxytocin that acts as
antagonist at the oxytocin receptors.
 In clinical trials, it has been found to suppress
premature uterine contractions and postpone preterm
delivery with fewer cardiovascular and metabolic
complications than β2 adrenergic agonists.
In Europe and UK it is available for inhibition of
labour between 24–33 weeks of gestation, and may
offer better benefit: risk ratio than other tocolytics.
A suggested dose of atosiban of an initial bolus of
6.75mg over 1 minute, followed by infusion of 18mg/hr
for 3hours, then 6mg/hr for up to 45 hours(to a
maximum of 330mg). GTG guidelines
Duration of treatment is 48hours.
ADRENERGIC AGONISTS
Ritodrine, the β2 selective agonist having more
prominent uterine relaxant action is approved to
suppress premature labour.
For dependable action it is started as 50 µg/min i.v.
infusion, the rate is increased every 10 min till uterine
contractions cease or maternal HR rises to 120/min.
Contractions are kept suppressed by continuing i.v.
infusion or by 10 mg i.m. 4–6 hourly followed by 10 mg
oral 4–6 hourly. However, treatment beyond 48 hours
is not recommended, since risk to mother increases
and benefit is uncertain.
SIDE EFFECTS AND COMPLICATIONS OF β-MIMETIC
TOCOLYSIS.
Maternal tachycardia, chest discomfort, palpitation,
tremor.
Headache, nasal congestion, nausea and vomiting.
Hyperkalemia and
Hyperglycemia.
Cardiopulmonary Complications of β-Mimetics.
Signs of excessive blood loss (e.g., maternal and fetal
tachycardia) are masked by β-mimetics, so their use
may be dangerous in women with antepartum
hemorrhage.
The most important steps to prevent cardiac
complications are to
 Exclude patients with prior cardiac disease and,
 Limit infusion rates so that maternal pulse does not
exceed 130 beats/min.
Tocolysis should be discontinued and oxygen
administered whenever a patient develops chest pain
during β-mimetic therapy.
An ECG is indicated if there is no response to oxygen
and cessation of β-mimetic therapy.
Restricting the duration of treatment to less than 24
hours, careful attention to fluid status, and detection
of complicating conditions such as intrauterine
infection may reduce this risk.
Metabolic Complications
β-Mimetic agents induce transient hyperglycemia and
hypokalemia during treatment.
Measurement of glucose and potassium before
initiating therapy and, on occasion, during the first 24
hours of treatment is appropriate to identify
significant hyperglycemia (>180 mg/dL) or
hypokalemia (<2.5 mEq/L).
Neonatal Effects.
Neonatal hypoglycemia, hypocalcemia, and ileus may
follow treatment with β-mimetics and can be clinically
significant if the maternal infusion is not discontinued
2 hours or more before delivery.
β-sympathomimetic agents should not be used in
women with known or suspected heart disease, severe
preeclampsia or eclampsia, pregestational gestational
diabetes requiring insulin, or hyperthyroidism.
 These drugs are contraindicated when suspected
preterm labor is complicated by maternal fever, fetal
tachycardia, leukocytosis, or other signs of possible
chorioamnionitis.
 CYCLOOXYGENASE INHIBITORS
Prostaglandins are mediators of the final pathways of
uterine muscle contraction. Prostaglandins cause an
increase in free intracellular calcium levels in
myometrial cells and an increased activation of MLCK,
resulting in uterine contractions.
Prostaglandin synthase, also known as cyclooxygenase
(COX), converts arachidonic acid to prostaglandin G2.
Prostaglandin synthesis is reduced by the inhibition of
COX with nonsteroidal antiinflammatory drugs
(NSAIDs).
INDOMETHACIN
Indomethacin is the NSAID most often used as a
tocolytic, although it crosses the placenta.
Unlike aspirin, indomethacin binds reversibly to COX,
so that inhibition lasts only until the drug is cleared
metabolically.
Umbilical artery serum concentrations equal maternal
levels within 6 hours of oral administration.
The half-life in the mother is 4 to 5 hours, and in a
full-term infant it is 15 hours, but it is significantly
longer in preterm infants.
MATERNAL SIDE EFFECTS
Nausea, esophageal reflux, gastritis, and emesis.
platelet dysfunction (rarely of clinical significance in
patients without an underlying bleeding disorder).
Renal or hepatic disease.
Active peptic ulcer disease.
Poorly controlled hypertension, asthma.
FETAL SIDE EFFECTS
Three principal side effects raise concern
In utero constriction of the ductus
arteriosus,
Oligohydramnios, and
Neonatal pulmonary hypertension.
The ductal constriction occurs because formation of
prostacyclin and PGE2, which maintain ductal
vasodilation, is inhibited by indomethacin.
Doppler evidence of ductal constriction was found in
7 of 14 fetuses of women treated with indomethacin
between 27 and 31 weeks’ gestation, but it resolved
within 24 hours after the medication was
discontinued.
Primary pulmonary hypertension in the neonate is a
potentially fatal illness that has also been associated
with prolonged(>48 hr) indomethacin therapy.
Primary neonatal pulmonary hypertension has not
been reported within 24 to 48 hours of therapy
Oligohydramnios associated with indomethacin
tocolysis is due to reduced fetal urine production.
Prolonged treatment with indomethacin incurs a 7%
frequency of oligohydramnios.
Because of the effect on fetal urine production and
amniotic fluid volume, indomethacin may be an
appropriate tocolytic when preterm labor is
associated with polyhydramnios. Indomethacin has
been used to treat preterm labor in women with
polyhydramnios and for polyhydramnios without
labor.
TREATMENT PROTOCOL FOR INDOMETHACIN TOCOLYSIS.
1. Limit use to preterm labor before 32 weeks’ gestation in
women with normal amniotic fluid volume and normal renal
function.
2. Loading dose is 50 mg by mouth.
3. Give 25 mg orally every 6 hours for 48 hours.
4. If the drug is used beyond 48 to 72 hours, amniotic fluid
volume should be monitored serially with ultrasound, and
ductus arteriosus flow should be evaluated with Doppler
echocardiography. If amniotic fluid is significantly reduced or
the ductus is narrowed, the drug should be discontinued.
5. Discontinue therapy promptly if delivery seems imminent.
6. Fetal contraindications to the use of indomethacin include
renal anomalies, chorioamnionitis, oligohydramnios,
ductaldependent cardiac defects, and twin-twin transfusion
syndrome.
Use of a tocolytic drug is associated with a prolongation of
pregnancy for up to 7 days but with no significant effect on
preterm birth and no clear effect on perinatal or neonatal
morbidity.
However, tocolysis should be considered if the few days
gained would be put to good use, such as completing a
course of corticosteroids or in utero transfer.
Nifedipine and atosiban have comparable effectiveness
in delaying birth for up to seven days.
Compared with beta-agonists, nifedipine is associated
with improvement in neonatal outcome, although there
are no long-term data.