Drugs administered to mothers have the potential to cross the placenta and reach the fetus. Under particular circumstances, the comparison of the drug concentration in the maternal and fetal plasma may give an idea of the exposure of the fetus to the maternally administered drugs. In this review drugs are classified according to their type of transfer across the placenta. Several drugs rapidly cross the placenta and pharmacologically significant concentrations equilibrate in maternal and fetal plasma. Their transfer is termed ‘complete’. Other drugs cross the placenta incompletely, and their concentrations are lower in the fetal than in maternal plasma. The majority of drugs fit into 1 of these 2 groups. A limited number of drugs reach greater concentrations in fetal than maternal plasma. It is said that these drugs have an ‘exceeding’ transfer. The impression prevails that suxamethonium chloride (succinylcholine chloride) and doxorubicin do not cross the placenta. However, a careful analysis of the literature suggests that this impression is wrong and that all drugs cross the placenta, although the extent transfer varies considerably. The following parameters were considered as possible factors determining the extent of placental transfer: (i) the molecular weight of the drug; (ii) the pKa (pH at which the drug is 50% ionised); and (iii) the extent of drug binding to the plasma protein. Drugs with molecular weights greater than 500D have an incomplete transfer across the human placenta. Strongly dissociated acid drug molecules should have an incomplete transfer, but this does not seem to be an absolute rule. For example, ampicillin and methicillin transfer completely and they are strongly dissociated at physiological pH. The extent of drug binding to plasma protein does not influence the type of drug transfer across the human placenta.

Placental Transfer of Drugs Administered to the Mother

OBJECTIVE: Despite the widespread use of benzodiazepines during pregnancy and lactation, little information is available about their effect on the developing fetus and on nursing infants. The authors review what is currently known about the effects of benzodiazepine therapy on the fetus and on nursing infants. METHODS: A MEDLINE search of the literature between 1966 and 2000 was conducted with the terms "benzodiazepines," "diazepam," "chlordiazepoxide," "clonazepam," "lorazepam," "alprazolam," "pregnancy," "lactation," "fetus," and "neonates." RESULTS: Currently available information is insufficient to determine whether the potential benefits of benzodiazepines to the mother outweigh the risks to the fetus. The therapeutic value of a given drug must be weighed against theoretical adverse effects on the fetus before and after birth. The available literature suggests that it is safe to take diazepam during pregnancy but not during lactation because it can cause lethargy, sedation, and weight loss in infants...

/pdf/effects-of-commonly-used-benzodiazepines-on-the-fetus-the-1aedljtldj.pdf

Effects of commonly used benzodiazepines on the fetus, the neonate, and the nursing infant.

The effects of benzodiazepine use during pregnancy and lactation

Recent concern over toxic effects of drugs in newborns, infants and children have stressed the need for better knowledge of drug kinetics during development. The present review focuses on the available data on clinical pharmacokientics in the neonate. Despite the lack of systematic approaches on drug disposition during the first month of life, the body of data currently available indicates profound differences in drug disposition between neonates and older infants, children and adults. In terms of physiological and anatomical factors the neonate has to be considered as a 'unique drug recipient'. For all the specific variables which govern the drug kinetic pattern (absorption, blood esterase activity, plasma protein binding, metabolic degradation and renal excretion), there are clear difference between neonates and older infants and children. Such differences are not always unidirectional. In the case of absorption, they depend on the maturational stage, but more on the physico-chemical properties of the individual compound. Esterase activiy and renal excretion are also related to the physico-chemical properties of the drug, but are more clearly linked with the development stage. Plasma protein blinding is generally reduced, and depends on several factors, not all of which are as yet clearly identified and understood. Biotransformation activities are usually very low, but may be increased several-fold by exposure to inducing agents. Hydroxylating activity and conjugation with glucronic acid appear to be the two metabolic pathways which are most defective at birth, while sulphate and gylcine conjugation, and dealkylation activities are close to the adult pattern. The material reviewed is fragmentary and does not always permit a comparison of the data obtained in newborns with those reported for adults. Differences in the methodology used and in the kinetic criteria further complicate the matter. It is, however, clearly emerging that drug disposition may vary greatly in the newborn in relation to its developmental age. The reported differences may be relevant for clinical practice and stress the need for more detailed information on drug kinetics in the neonate. Such information may be achieved by carefully planned clinical trials, but more meaningfully, and more profitably for the individual patient, by a very carefully, well integrated monitoring of the neonate a risk. By such an approach, where drug plasma levels are related to drug effects and to the pathophysiological condition, the significance of various factors on drug disportion during development will be better clarified, thus allowing a more rational and safer therapy in the newborn.

Clincial pharmacokinetics in neonates.

Benzodiazepines: Clinical Pharmacology and Therapeutic Use

Diazepam (DZ) placental transfer in pregnant women at term, following single or repeated drug administration by various routes, was evaluated. DZ and its metabolite N-demethyldiazepam (NDZ) were constantly present in umbilical cord plasma at concentrations comparable to the mother's shortly after drug administration. N-methyloxazepam (MOX) was detected in cord plasma only in a limited number of cases following chronic DZ treatment. Postmortem analysis of fetal tissue concentrations showed accumulation of NDZ in heart and lungs. Differences in NDZ concentrations between venous cord (VC) and arterial cord (AC) plasms suggest metabolic degradation of DZ in the fetus. The DZ apparent plasma half-life in the newborn was found to be longer (31 plus or minus 2 hr) than previously observed in infants and children. The low drug clearance appears to be linked to reduced urinary excretion of hydroxylated metabolites, suggesting limited capability to dispose of DZ in the newborn.

Placental transfer of diazepam and its disposition in the newborn

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Placental transfer of diazepam and its disposition in the newborn

Placental transfer of diazepam and its disposition in the newborn