Clinical Pharmacokinetics in Pregnancy and Perinatology

Abstract

Local anaesthetic agents, both of the amide type (e.g., lidocaine, bupivacaine, etidocaine) and of the ester type (e.g., 2-chloroprocaine) are widely used to relieve pain in obstetric and gynaecological practice. The pharmacokinetics of these compounds are discussed in this review, with particular emphasis on the fetal exposure and its relationship to adverse effects on the fetus. 2-Chloroprocaine is rapidly hydrolyzed by esterases, and only traces of this compound reach the fetus, even following multiple injections, suggesting safety for the fetus. The main disadvantage of this compound is the short duration of action (0.5-1 h). The amide-type agents are active for longer time periods (up to several hours). The fetal/matemal total concentration ratios were approximately 0.3 for bupivacaine and etidocaine, 0.5 for lidocaine, 0.7 for mepivacaine, and 1 for prilocaine. The low ratios of bupivacaine and etidocaine result from extensive binding (90%) of these drugs to maternal a(1)-acid glycoprotein which exceeds corresponding fetal protein binding (50%). These low fetal/matemal total concentration ratios cannot be equated with fetal safety, because fetal side effects are better related to the free drug levels. Since the amide- type anaesthetics are weak bases, fetal acidosis will increase the matemal/fetal pH gradient and will result in accumulation of free drug in the fetus and possible fetal side effects. Addition of epinephrine to the injection solution reduces the maternal blood levels of the amide-type compounds, but apparently not the fetal levels to the same extent. Because of possible unwanted effects of epinephrine (decreased uterine blood flow), the addition of this compound is not generally accepted to be of advantage. Paracervical blockade may result in elevated fetal blood levels (possibly by transarterial diffusion into uterine arteries) and possibly fetal bradycardia.

Antibiotic Use in Pregnancy and Lactation

“…In 1 case (clindamycin), the standard pharmacokinetic parameters did not change appreciably during the first, second, or third trimester of pregnancy (Table 2). 10 No adverse effects seen in nursing infants whose mothers have been treated with amoxicillin. 5 Excreted in human breast milk in small amounts.…”

“…6,11 Penicillins are primarily renally excreted via tubular secretion and glomerular filtration. 5,7,10,33,34,35 Penicillins are transferred to the fetus and amniotic fluid reaching therapeutic levels. 6,11 Penicillin VK Gram-positive aerobes including most streptococci/ enterococci, grampositive anaerobes, gram negatives Crosses the human placenta readily.…”

“…58 The frequency of 1st-trimester penicillin use was no greater than expected in a prospective study of 194 infants with major malformations born in Sweden (1963)(1964)(1965). 10,44,58,99,102 No teratogenicity in mice administered up to 500 units/g on gestation day 14. Rate of 1st-trimester penicillin use was no greater than expected in a case-control study of 538 infants with neural tube defects and 539 controls in California from 1989 to 1991 (no increased risk).…”

Headache in Challenging and Special Circumstances: Pregnancy and Lactation

“…[56] Lidocaine and bupivacaine which are well studied in pregnancy are commonly used in dentistry and obstetric anesthesia. [57] According to retrospective, uncontrolled case series none of the patients experienced any major maternal or fetal adverse effects related to these drugs. Peripheral nerve blocks are used for both short-term migraine prophylaxis as well as the treatment of status migrainosus.…”

In Utero and in Vitro Exposure to β-Lactams Impair Kidney Development in the Rat

“…They are widely prescribed during pregnancy because they are considered safe (reviewed in references (2) and (3). However, like most drugs, ␤-lactam antibiotics cross the human placenta and therefore the fetus is exposed to these molecules (4,5). Although it is well known that these drugs are not teratogenic, the absolute lack of toxicity of ␤-lactam antibiotics to the fetus remains to be determined.…”