TOCOLYTIC DRUGS

UPDATE

ByDr.Asmaa Al sanjary

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 .

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.

Concern to be takenbefore choosing a drug :

• 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

B2 agonistAre 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 arecompared 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

adverseeffects have been reported following beta-agonists useand a few maternal deaths associated with the use of these drugs were reported.

Pulmonary edema is a well-documentedComplication , 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

withplacebo).

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.

Oxytocin receptor antagonist

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 profileand seems to be an adequate therapeutic

choice for Effective tocolysis with a low maternal and fetal adverse effects profile.

Atosiban represents an advance in currently availabletocolytics, and should be considered a first-line tocolyticfor the management of SPTL.Atosiban is licensed in Europe for treatment of SPTL.The recommended dosage and administration schedulefor atosiban is a three-step procedure.

Duration of treatment should not exceed 48 h and thetotal dose given during a full course should preferablynot exceed 330 mg of atosiban. In the early gestationalage with or without PPROM, the use of atosiban can beprolonged for a further few days without any significantside 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

whichthe bolus dose is administered.

Mg sulphate 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 .

There is no evidence any more to recommend this drug as a first-line tocolytic agent .

Indomethacin 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 meta-analysis to be an efficient tocolytic drug compared to placebo, significantly delaying preterm delivery .

It can be administrated rectally or orally.

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.

Ca-channels blockers 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 isgiven 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

Nitric oxide donor 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

there is no large randomized studies available,

NO is not used in clinical routine. Its use still exparmental.

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 ofreported cases of symptomatic hypocalcemia, Neuromuscular blockade, and cardiac toxicity,including maternal death.

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.

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.

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