Pharmacokinetics of tocolytic agents

Tocolytic agents are drugs designed to inhibit contractions of myometrial smooth muscle cells. Such an effect has been demonstrated in vitro or in vivo for several pharmacological agents, including beta-adrenergic agonists, calcium channel antagonists, oxytocin antagonists, NSAIDs and magnesium sulfate. However, the aim of tocolysis is not only to stop uterine contractions or to prevent preterm delivery, but to prevent perinatal morbidity and mortality associated with preterm birth.. The achievement of this goal has not yet been clearly demonstrated for any of the drugs available, and the use of tocolytic agents may appear controversial. Therefore, it is important to avoid maternal and fetal toxicity when tocolytic agents are used. During pregnancy, all steps of drug pharmacokinetics are altered. Absorption of drugs administered orally is limited because of delayed stomach emptying and reduced intestinal motility. The volume of distribution of drugs is increased. The metabolic activity of the liver is increased, accelerating the metabolism of lipophilic drugs. Renal filtration is increased, leading to enhanced renal elimination of water-soluble drugs. These modifications are generally responsible for reduced plasma concentration and reduced half-life of most drugs. These specific modifications have to be taken into account when using a drug in pregnant women. The aim of this review is to provide the reader with pharmacological data about drugs currently used to treat preterm labour. Such data in pregnant women may affect the choice of optimal drug dosage and route of administration. Preterm birth is the leading cause of neonatal morbidity and mortality in infants without anomalies. Preterm delivery of infants before 37 weeks of gestation complicates 8-10% of births in the US, and the majority of preterm births are secondary to preterm labour (spontaneous preterm deliveries). ([1]) During the past 40 years, a number of pharmacological agents have been used to treat preterm contraction's in order to prevent preterm delivery. These tocolytic drugs are widely used by obstetricians, yet the incidence of, preterm delivery remains unchanged. Tocolysis is a purely symptomatic treatment of preterm labour, since the aetiology of the preterm birth (such as infection or cervical incompetence) is often unknown or only, discovered after delivery.([1]) Moreover, the efficacy of tocolysis remains controversial since a recent systematic review did not provide evidence of a significant improvement in neonatal morbidity or mortality. ([2]) For several reasons, it is difficult to assess the efficacy of tocolytic agents. Firstly, the criteria used to define preterm labour are heterogeneous in different studies. Secondly, in most placebo-controlled trials, almost 70% of patients receiving placebo are undelivered 48 hours after inclusion. Thus, trying to demonstrate benefits of tocolytic agents on neonatal morbidity requires large numbers of patients in each group. Thirdly, there are wide variations among studies in the outcomes evaluated. Although the final objective should be the prevention of perinatal morbidity and mortality associated with, preterm delivery, in most studies the main outcome was prolongation of pregnancy. The result is an excessive use of tocolytic agents in clinical practice, exposing patients and fetuses to inappropriate risks and adverse effects. The main improvements in neonatal outcome in the last few years have been obtained by the use of corticosteroids for fetal lung maturation ([3-5]) and by prenatal transfer to, centres with neonatal intensive card facilities ([3-5]) in case of very preterm deliveries. It is believed that tocolytic therapy, by prolonging pregnancy, even for a short period of time, may be useful in allowing, these measures to be performed.([6]) The aim of this manuscript is to provide the reader with pharmacological data about drugs currently used to treat preterm labour. Such data in Pregnant women may affect the choice of optimal drug dosage and route of administration. During Pregnancy, all steps of drug pharmacokinetics are altered. ([7]) Absorption of drugs administered orally is limited because,of delayed stomach emptying and reduced intestinal motility. The volume of distribution of drugs is increased.([8]) The metabolic activity of the liver is increased, accelerating metabolism of lipophilic drugs. Renal filtration is increased, leading to enhanced renal elimination of water-soluble drugs. These modifications are generally responsible for reduced plasma concentration and reduced half-life of most drugs. Most of the drugs used to inhibit preterm labour in clinical practice will be discussed in this review: P-adrenergic agonists, calcium channel antagonists, oxytocin antagonists, NSAIDs and magnesium sulfate. However, some of these drugs cannot be considered as first-line therapeutic options, since they are either effective but associated with severe potential adverse effects (NSAIDs) or their effectiveness has not been demonstrated (magnesium sulfate). Treatments used for the prevention of preterm labour will not be considered in this paper. A literature search of MEDLINE and the Cochrane Library was conducted for the years 1960 to June 2002 with regard to the pharmacokinetics of tocolytic agents. The keywords used were: 'tocolytics', 'pharmacokinetics', 'ritodrine', 'terbutaline', 'salbutamol', 'magnesium sulfate', 'nonsteroidal anti-inflammatory', 'indomethacin', 'nifedipine', 'nicardipine' and 'atosiban'. The reference lists of identified articles were examined to find additional relevant studies.