Fetal and Neonatal Effects of the
Beta-Adrenoceptor Blocking Agents

Mj, Boutroy

doi:10.1159/000457747

Cited by 33 publications

(16 citation statements)

References 11 publications

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“…However, adverse effects of 0-receptor blocking drugs in the human infant have also been a source of concern (29,30), so our results suggest that caution should be exercised in the passive administration of Padrenergic drugs such as ritodrine to the fetus over prolonged periods of time. Such infants should clearly be provided with the same level of care as that recommended for infants from Pblocked pregnancies (30).…”

Section: Discussionmentioning

confidence: 93%

“…Although there has been concern about possible cardiovascular complications in the fetus from P-sympathomimetic therapy for tocolysis (23) and effects of p-agonists on the incidence or respiratory distress and perinatal hypoglycemia (l,28) have been reported, the incidence of long-term complications appears low (28). However, adverse effects of 0-receptor blocking drugs in the human infant have also been a source of concern (29,30), so our results suggest that caution should be exercised in the passive administration of Padrenergic drugs such as ritodrine to the fetus over prolonged periods of time. Such infants should clearly be provided with the same level of care as that recommended for infants from Pblocked pregnancies (30).…”

Section: Discussionmentioning

confidence: 99%

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Desensitization of β-Receptor Mediated Responses to Epinephrine in Fetal Lambs by Prolonged Ritodrine Administration

1990

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ABSTRACT. During prolonged administration of @-agonists such as ritodrine directly to chronically cannulated fetal lambs, the cardiovascular, metabolic, and endocrine changes observed during the 1st day of administration, lessen and return to normal within 3-4 d despite continuing drug administration. In our investigation, heart rate, plasma FFA, lactate, glucose, and insulin concentrations all increased significantly during the 1st day of ritodrine infusion (10 wg/min), whereas blood Poz and base excess were significantly decreased. After 3 d, despite continued drug infusion, all these changes had ameliorated. To examine the hypothesis that this tachyphylaxis to ritodrine also results in decreased sensitivity to endogenous catecholamines, epinephrine (1 pg/min i.v. for 60 min, then 2 pg/min i.v. for a further 60 min) was infused into fetal lambs (124-130 d gestation) 1 d before, then 5 f 1 d after, and again 10 f 1 d after beginning ritodrine infusion. Before ritodrine administration, epinephrine significantly increased plasma FFA, lactate, glucose, and glucagon concentrations and decreased insulin. However, after ritodrine treatment for either 5 +. 1 or 10 f 1 d, epinephrine resulted in no significant increases in FFA or glucagon, and those in lactate and glucose were significantly reduced. Decreases in insulin during epinephrine administration were unchanged by ritodrine. Initial responses of mean arterial pressure and heart rate to epinephrine were significantly greater during prolonged ritodrine treatment. Fetal responses to epinephrine mediated through @-adrenergic receDtor mechanisms were clearlv decreased when administration of @-agonists was prolonged beyond 24 h. (Pediatr Res 28: 388-393,1990) typical of prolonged stimulation of P-adrenergic receptor mechanisms. Hyperglycemia, hyperlactacidemia, and hyperinsulinemia occur and acid-base balance is severely taxed during the 1st 48-72 h of infusion. Further, Warburton et al. (7) have observed that the hyperglycemia is associated with substantial depletion of hepatic glycogen reserves after 24 h administration. Also, both we (6) and Warburton et al. (8) have shown that administration of ritodrine for 24 h or longer results in the development of marked hypoxemia at least as severe as that seen in fetal lambs during prolonged hyperglycemia and/or hyperinsulinemia (9, 10). After administration of the drug for more than 48 h, these changes moderate (6). It appears that it is only the development of tachyphylaxis to the drug that permits the restoration of homeostasis during more prolonged administration. Indeed, Warburton et al. (1 1, 12) have shown that there is already a very marked reduction in the P-adrenergic receptor population of fetal lung tissue after 24 h of ritodrine administration. More widespread changes in sensitivity of P-adrenergic receptor mechanisms have not been investigated.Although this reduction in sensitivity may permit fetal survival in the face of prolonged ritodrine treatment, we questioned whether it might have other less desira...

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Section: Discussionmentioning

confidence: 93%

Section: Discussionmentioning

confidence: 99%

Desensitization of β-Receptor Mediated Responses to Epinephrine in Fetal Lambs by Prolonged Ritodrine Administration

1990

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“…␤ -Blockers cross the placenta and reach the fetus at concentrations very close to those present in the pregnant mother [70] . Our study provides evidence that ␤ AR blockers, particularly ␤ 1 AR antagonists, exacerbate hypoxia-induced bradycardia in the early fetus.…”

Section: Clinical Relevancementioning

confidence: 99%

β<sub>1</sub>-Adrenergic Receptors Maintain Fetal Heart Rate and Survival

et al. 2006

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β-Adrenergic receptor (βAR) activation has been shown to maintain heart rate during hypoxia and to rescue the fetus from the fetal lethality that occurs in the absence of norepinephrine. This study examines whether the same subtype of βAR is responsible for survival and heart rate regulation. It also investigates which βARs are located on the early fetal heart and whether they can be directly activated during hypoxia. Cultured E12.5 mouse fetuses were treated with subtype-specific βAR antagonists to pharmacologically block βARs during a hypoxic insult. Hypoxia alone reduced heart rate by 35–40% compared to prehypoxic levels. During hypoxia, heart rate was further reduced by 31% in the presence of a β₁AR antagonist, CGP20712A, at 100 nM, but not with a β₂ (ICI118551)- or a β₃ (SR59230A)-specific antagonist at 100 nM. Survival in utero was also mediated by β₁ARs. A β₁ partial agonist, xamoterol, rescued 74% of catecholamine-deficient (tyrosine-hydroxylase-null) pups to birth, a survival rate equivalent to that with a nonspecific βAR agonist, isoproterenol (87%). Receptor autoradiography showed that β₁ARs were only found on the mouse heart at E12.5, while β₂ARs were localized to the liver and vasculature. To determine if the response to hypoxia was intrinsic to the heart, isolated fetal hearts were incubated under hypoxic conditions in the presence of a βAR agonist. Heart rate was reduced to 25–30% by hypoxia alone, but was restored to 63% of prehypoxic levels with 100 nM isoproterenol. Restoration was completely prevented if β₁ARs were blocked with CGP20712A at 300 nM, a concentration that blocks β₁ARs, but not β₂- or β₃ARs. Our results demonstrate that β₁ARs are located on the heart of early fetal mice and that β₁AR stimulation maintains fetal heart rate during hypoxia and mediates survival in vivo.

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“…Several controlled studies have shown their efficacy and safety in pregnant women, without any specific risk for the fetus (Dubois et al 1983;Fidler et al 1983;Livingstone et al 1983;Olofsson et al 1986;Plouin et al 1988). However, very little information is available (for review: see Morselli et al 1989) on the pahrmacokinetics of these agents in the neonate, or on the possible relationship between neonatal drug concentrations and the cardiovascular effects observed in a limited number of cases 48-72 h after birth (Boutroy et al 1987).…”

Section: Discussionmentioning

confidence: 99%

Placental transfer and perinatal pharmacokinetics of betaxolol

Morselli¹,

Boutroy

Bianchetti³

et al. 1990

Eur J Clin Pharmacol

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Betaxolol levels in blood were monitored in the perinatal period in 28 pregnant hypertensive women and in their babies. In the mothers betaxolol concentrations at delivery ranged from less than 1 to 115 ng.ml-1 after doses of 10 to 40 mg.day-1. The apparent blood half-life was 15.6 to 22.1 h mean (19 h). Umbilical cord levels indicated a rapid equilibrium between fetal and maternal units (ratio 0.93) within few hours after dosing. Milk betaxolol concentrations, measured in few cases, exceeded those in blood by a factor of 3. Amniotic fluid concentrations were similar to those observed in maternal venous blood and umbilical cord blood. In neonates, the blood betaxolol half-life ranged from 14.8 to 38.5 h, with a definite trend towards a negative correlation with gestational age. A 11-61% rise in the betaxolol concentration was observed in 64% of the neonates during the first 12 h of extrauterine life. The data indicate that betaxolol kinetics is not altered in pregnant women and they stress the need for careful and prolonged (72-96 h) intensive monitoring of neonates born to hypertensive mothers treated with beta-blocking agents.

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Fetal and Neonatal Effects of the Beta-Adrenoceptor Blocking Agents

Cited by 33 publications

References 11 publications

Desensitization of β-Receptor Mediated Responses to Epinephrine in Fetal Lambs by Prolonged Ritodrine Administration

Desensitization of β-Receptor Mediated Responses to Epinephrine in Fetal Lambs by Prolonged Ritodrine Administration

β<sub>1</sub>-Adrenergic Receptors Maintain Fetal Heart Rate and Survival

Placental transfer and perinatal pharmacokinetics of betaxolol

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