283 adrenergic receptor blockers

Pharmacology

;i-blockers (acebutolol, alprenolol, atenolol, betaxolol, bisoprolol, Celiprolol, Carvedilol, esniolol, labetalol, rnetoprolol, nadolol, nebivolol, oxprenolol, pindolol, propranolol, sotalol, and timolol) have a wide spectrum of activity, and are often used to treat hypertension. There are two types of (3-receptors; i^-receptors predominate in the heart, and ¿¿-receptors mediate relaxation (dilatation) of vascular and other smooth muscle (e.g. in the airways and blood vessels). Metoprolol is ii-specific, whereas the classic i-blockers such as propranolol and oxprenolol have both rtj and ¿2 activity. Labetalol has both ¿- and a-receptor blocking activity, and has been successfully used in a number of pregnancies (Pickles 1992, Plouin 1990, 1987). All |3-blockers cross the placenta.

Toxicology

To date, there is no clear evidence to indicate that ¿-blockers are teratogens (Magee 2000). There have been occasional reports of congenital anomalies following in utero exposure to ¿-blockers, but no causal relationship has been proven.

A report on 105 newborns exposed to atenolol in the first trimester described 12 infants with birth defects (Rosa, cited in Briggs 2005). However, there was no pattern of malformations, and the data have not been confirmed by other studies.

In the TIS in Berlin, we have analyzed more than 200 prospectively ascertained pregnancies which were exposed to metoprolol in the first trimester. Among 175 live births there were 7 with major malformations (4 percent): cleft palate (n = 2), atrial septal defect (n = 2), stenosis of pulmonary artery (n = 1), diaphragmatic hernia (/i = 1), and polycystic kidney (n = 1).

Statistically significant growth restriction was described in a number of studies on atenolol (Tabacova 2003A, Easterling 1999A). Some of these investigations found a stronger effect of atenolol compared with acebutolol, pindolol, and labetalol. Growth restriction could not be confirmed when compared with a non-exposed control group (Lydakis 1999, Katz 1987), but there is a continuing debate whether other ¿-blockers might produce the same effects as atenolol (Magee 2003). It is difficult to determine whether atenolol itself or the underlying maternal disease has the potential to cause a reduction of placental perfusion. Intrauterine growth restriction may be attributed to reduced substrate availability due to the lowering of blood sugar as a result of ¿-receptor blockade. Postnatal growth in the first year of life and other developmental landmarks seem not to be adversely affected (Reynolds 1984).

Bayliss (2002) analyzed 491 pregnant hypertensive women, of whom 302 took at least one antihypertensive drug; the remaining 189 women, without medication, were the controls. Only those newborns who were exposed from conception or from the first trimester until birth (n = 40) had a significant lower birth weight.

Atenolol, only taken in the second trimester, did not produce such results, tn any case, and independent of the mother's medication, pre-eclampsia led to growth restriction.

Some studies have compared i.v. labetalol for pre-eclampsia with nifedipine, and described a favorable outcome (Scardo 1999, Vermillion 1999). Meta-analysis revealed advantages of i.v. labetalol compared with dihydralazine or diazoxide in cases of severe late-onset hypertension in late pregnancy (Magee 2000).

There is insufficient experience of use in pregnancy of alprenolol, betaxolol, bopindolol, bupranolol, carazolol, carteolol, carvedilol, celiprolol, mepindolol, nadolol, nebivolol, penbutolol, talinolol, and tertatolol to determine their safety.

Although a significant teratogenic risk is not expected with A-blockcrs, there is a theoretical risk of neonatal i-receptor blockade -leading to neonatal bradycardia, hypotension, and hypoglycemia (Rubin 1983A. Dumez 1981). Respiratory distress and apnea have been reported following in utero exposure to propranolol until birth, but such adverse effects are rare (Tumstall 1969). There are conflicting opinions regarding the safety of stopping medication with ,1-blockers 24-48 hours before delivery. Neonatal symptoms of ¡i-blockade are usually mild and improve within 48 hours of delivery with no long-term effects. Nevertheless, obstetricians, midwives, and pediatricians should be informed about maternal medication and made aware of the possibility of neonatal toxicity.

There is a theoretical risk of intensifying premature uterine contractions as a result of receptor blockers. However, no negative influence on inhibition of contractions was described as a result of giving preceptor blockers during a tocolysis with .-^-sympathomimetics (Trolp 1980).

Recommendation, ^-receptor blockers such as labetalol, propranolol, and metoprolol, which have been in long-term use, are among the first-line drugs of choice for treating hypertension in pregnancy. Treatment with other i-blockers with less information on its safe use in pregnancy is not an indication for invasive diagnostic procedures or for termination of pregnancy. It is important to be aware of pharmacological effects such as decreased heart rate, hypoglycemia, and respiratory problems, particularly in premature neonates, when treatment with ^-blockers continues until birth.

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