ReviewAtenolol: pharmacokinetic/dynamic aspects of comparative developmental toxicity☆
Introduction
Atenolol is a cardioselective β-adrenoreceptor blocking agent, used for treatment of hypertension, including hypertension in pregnancy. Beta-adrenoreceptor antagonists have been implicated in the production of intrauterine growth retardation and a considerable range of neonatal problems including hypoglycemia, bradycardia, respiratory depression and death [1], [2]. The relationship between these complications and drug administration is often difficult to evaluate because of the anecdotal or retrospective nature of observations. In addition, since β-blockers are used in pregnancies having a major complication (e.g. severe hypertension), it can be very difficult to differentiate drug effects on the fetus from those caused by the underlying maternal disease.
This paper reviews pharmacokinetic and pharmacodynamic issues relevant to atenolol prenatal toxicity in humans and in experimental animal species with the aim of better understanding the origin of adverse developmental outcomes that have been associated with atenolol exposures in pregnancy.
Section snippets
General
Chemically, atenolol is a phenylacetamide [(4–2′-hydroxy-3′-isopropyl-aminopropoxy) phenylacetamide]. It is a relatively polar, hydrophilic compound. In adult nonpregnant subjects, the disposition of atenolol has been studied in humans and in several animal species: rats, mice, rabbits, dogs, and rhesus monkeys [3], [4].
The absorption of the drug upon oral administration in humans and most laboratory animal species is rapid but incomplete. Due to incomplete intestinal absorption, the systemic
General
Atenolol is a cardioselective beta1-adrenoreceptor blocking agent without intrinsic sympathomimetic activity. It has a markedly greater effect on cardiac than bronchial or vascular adrenoreceptors [22], [23] and reduces blood pressure mainly by reducing cardiac output, in contrast to the nonselective β-blockers that reduce blood pressure mainly by decreasing the peripheral vascular resistance [24]. Atenolol mainly causes its hypotensive effect by decreasing heart rate and cardiac contractility
Summary and conclusion
The comparability of developmental effects of atenolol in humans and in animal models is affected by animal/human pharmacokinetic/dynamic differences. Because of considerable differences in atenolol gastrointestinal absorption in dogs versus other animal species and humans, data collected in the dog need to be interpreted with consideration of the internal dose for extrapolation to humans if this experimental model is used for predicting human developmental effects. Although atenolol absorption
Acknowledgments
The authors are grateful to Drs. William Slikker, Deborah Hansen, John Young, National Center for Toxicological Research, Jefferson, AR, and Dr Hugh Barton, EPA, Research Triangle Park, NC, who have reviewed an earlier version of this paper.
References (73)
- et al.
comparison of the actions of ICI 66 082, and propranolol on cardiac, and peripheral adrenoreceptors
Eur J Pharmacol
(1975) - et al.
Uterine and fetal hemodynamics and fetal cardiac function after atenolol and pindolol infusion
Eur J Obstet Gynecol Reprod Biol
(1995) - et al.
Effect of ICI 66 082, a beta adrenoreceptor blocking drug, on blood glucose in the rat
Europ J Pharm
(1975) - et al.
Beta-adrenergic blockers in pregnancy
Am Heart J
(1988) - et al.
Experiments with pharmacologic sympatholysis in the gravid
Am J Obstet Gynecol
(1967) - et al.
Effect of atenolol on birth weight
Am J Cardiol
(1997) - et al.
Inhibitory effects of β-adrenoreceptor antagonist, atenolol, on the thromboxane system in the kidney of spontaneously hypertensive rats
Prostaglandins Leucot Essent Fatty Acids
(1991) - et al.
Behavioral and biochemical studies in rats following prenatal treatment with β-adrenoreceptor antagonists
Eur J Pharmacol
(1991) - et al.
Myometrial and cardiovascular effects of an adrenergic blocking drug in human pregnancy
Am J Obstet Gynecol
(1968) - et al.
Obstetric aspects of the use in pregnancy-associated hypertension of the β-adrenoceptor antagonist atenolol
Am J Obstet Gynecol
(1984)
Effect of propranolol infusion on the umbilical and uterine circulations of pregnant sheep
Am J Obstet Gynecol
Maternal and fetal cardiovascular indices during fetal hypoxia due to cord compression in chronically canulated sheep. I. Responses to timolol
Am J Obstet Gynecol
Teratology and drugs in pregnancy and lactation
Disposition and metabolism of atenolol in animals
Xenobiotica
Metabolism of atenolol in man Xenobiotica
Clinical pharmacologic observations on atenolol, a β-adrenoreceptor blocker
Clin Pharmac Ther
The biological an clinical effects of atenolol (Tenormin), a cardioselective β-antagonist
Comparison between the acute hemodynamic effects and brain penetration of atenolol and metoprolol
J Cardiovasc Pharmacol
Beta blockers and the central nervous system (CNS)
Protein binding of atenolol and propranolol to human serum albumin and in human plasma
Br J Clin Pharmac
Review of clinical pharmacology of atenolol
Proc R Soc Med
Human pharmacokinetic and pharmacodynamic studies on atenolol (ICI 66082) a new cardioselective β-adrenergic receptor blocking drug
Br J Clin Pharmac
Studies on the pharmacokinetics and pharmacodynamics of atenolol in man
Eur J Clin Pharmacol
Relationship between blood level of atenolol and pharmacologic effect
Clin Pharm Ther
The pharmacokinetics of tenormin in patients suffering from renal insufficiency
Eur J Clin Pharmacol
Atenolol in the treatment of pregnancy-induced hypertension
J Clin Pharmac
Fetal and neonatal effects of the β-adrenoreceptor blocking agents
Dev Pharmacol Ther
Action of several β-adrenoreceptor drugs in the pregnant sheep and foetus
Br J Pharmac
Transplacental passage and breast milk accumulation of atenolol in humans
Drugs
Hypertension in pregnancyevaluation of two beta blockers atenolol and labetalol
Eur Heart J
Transplacental passage of atenolol in man
Eur J Clin Pharmacol
Pharmacokinetics of atenolol in pregnancy and lactation
Drugs
Cardiac and bronchial beta adrenoceptor antagonistic potencies of atenolol, metoprolol, acebutolol, practolol, propranolol and pindolol in the anesthetised dog
Clin Exp Pharmacol Physiol
Influence of the new beta sympatholytic agent, ICI 66 082, on haemodynamics and cardiac contractility with and without experimental coronary ligation
Verh Deutch Gerzs Inn Med
Haemodynamic long term effects of a new beta adrenoreceptor blocking drug, atenolol (ICI 66 082), in essential hypertension
Brit J Clin Pharmacol
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