Biological basis of therapeutic agents for preterm labour
In recent times, the prevention, prediction and treatment of preterm
labour has remained a
major focus for contemporary research in obstetrics (83). Generally, the
use of tocolytics has become a fundamental pharmacological therapy in
the clinical management of preterm labour(84). The biological basis for
the use of tocolytics is to delay delivery for at least 48hours to allow
for corticosteroids and magnesium sulphate administration to enhance
foetal lung maturation and prevention cerebral palsy respectively and
transfer to a tertiary healthcare facility with neonatal intensive care
facilities(83,84).
Proinflammatory cytokines such as IL-1β, IL-6, and IL-8 have been
strongly associated with cervical dilation in preterm labour and
medications the decrease the concentration of these mediators
constitutes potential preventive interventions(72). The common
therapeutic agents which are currently used to abort uterine
contractions or maintain uterine quiescence include beta adrenergic
receptor agonists (ritodrine, isoxsuprine, salbutamol, terbutaline),
prostaglandin -Synthase inbibitors [including NSAIDS (e.g
indomethacin) and COX-2 inhibitors (e.g Celecoxib)], oxytocin receptor
antagonists (atosiban), calcium channel blockers (nifedipine) and
Magnesium sulphate. Tocolytics are usually administered as a monotherapy
although a combination of more than one agent maybe required in some
cases. However, a recent systematic review by Vogel et al did not
support the use of a polytherapy of tocolytics over monotherapy and this
is partly due to lack of trials of combination regimens of commonly used
tocolytics(85).
Beta agonists (betamimetics) bind to beta 2 adrenergic receptors on
surface membranous myometrial smooth muscle cells which activate adenyl
cyclase leading to increased intracellular levels of cAMPs and
activation of protein kinase A. Increased cAMPs levels decrease
intracellular calcium which specifically suppresses spontaneous and
oxytocin-induced uterine contractions. Three different subtypes of beta
adrenergic receptors are located in the uterus and beta 2 adrenergic
receptors constitutes approximately 80%(86). However, the use of beta 2
adrenergic receptors is associated significant maternal side effects
such as palpitations, chest pain, breastlessness and pulmonary oedema in
severe cases which limits their clinical use for extended duration(86).
Atosiban is a nona-peptide, desamino-oxytocin analogue and a competitive
vasopressin/oxytocin receptor antagonist(87). Atosiban blocks oxytocin
receptors and prevents oxytocin-induced hydrolysis of
phosphatidylinositol 4,5-bisphosphate (PIP2) to IP3 and calcium efflux
into the cytoplasm(88). Thus, it inhibits signalling transduction on the
uterine smooth muscle leading to uterine relaxation (83,89). Atosiban
has minimal side effects with higher safety profile as compared to the
other tocolytics(90).
Selective COX-2 inhibitors such as celecoxib and non-specific COX
inhibitors such as indomethacin which are prostaglandin synthase-2
inhibitors inhibit the synthesis of prostaglandins (e.g. PGF2α & PGE2)
but do not affect the production of pro-inflammatory mediators (e.g.
IL-1β, IL-6, and TNFα) because the action of pro-inflammatory mediators
is upstream of COX-2 expression(91,92). Prostaglandins induce uterine
contraction via facilitation of myometrial gap junction formation and
increasing the concentration of intracellular calcium concentration.
Therefore, prostaglandin synthase inhibitors are considered effective
tocolytics. However, their usage is limited because they cause premature
constriction of the ductus arteriosus, inhibit platelets aggregation and
impair renal function and decreased urine production resulting in
oligohydramnios. Therefore, the duration of indomethacin use should be
restricted and limited to gestational age of 32 weeks(93).
Magnesium sulphate is used broadly as a tocolytic and proven to be more
effective in fetal neuroprotection and preventing cerebral palsy(94,95).
Magnesium sulphate competitively blocks intracellular calcium influx and
activation of myosin light chain kinase leading to decreased myometrial
contractility. It also inhibits acetyl choline release by competing with
calcium at the motor end plate of the neuromuscular junction. Perhaps,
its usage is not primarily intended to delay delivery but to prevent
cerebral palsy via neuroprotection(94–97). The common side effects
include flushing, respiratory depression and cardiac arrest(88). Based
on our review, all the tocolytic agents in recent use appear to act on
areas that interfere with either calcium entry or prostaglandins
production which are downstream of pro-inflammatory mediators’
production.