Antihypertensive Treatment of Pre-eclampsia: pharmacological aspects of ketanserin and nicardipine

Pre-eclampsia is a disease occurring in 2-8% of the pregnant women and it forms one of the leading causes of maternal and neonatal mortality and morbidity during pregnancy. The main clinical characteristics of pre-eclamptic patients are elevated blood pressure and proteinuria, occurring after the twentieth week of gestation. Treatment with antihypertensive drugs is indicated to prevent maternal complications like organ failure or cerebral haemorrhages, and, in selected cases, to prolong the pregnancy to improve neonatal outcome. In this thesis, the efficacy and safety in pre-eclampsia of two new antihypertensive drugs, the 5-HT2A receptor antagonist ketanserin and the calcium-channel blocking agent nicardipine, are studied. Intravenous administration of ketanserin to 47 early, onset, pre- eclamptic patients showed that an adequate antihypertensive response could not be obtained with ketanserin in one third of the patients, despite maximum dosages. High plasma concentrations were obtained in almost all patients, which renders a pharmacokinetic cause of the lack of response unlikely. To study the role of pharmacodynamics, an in vitro study on maternal resistance arteries and umbilical cord arteries was conducted. No differences in functionality of 5HT2A receptors were found between pre-eclamptic and normotensive pregnant women, indicating that a prominent role for 5HT2A receptors in pre-eclampsia seems to be unlikely. To study the safety of use of ketanserin during pregnancy, the transfer of ketanserin from mother to foetus through the placenta was determined. A high transplacental transmission of ketanserin was found but fortunately, an in vitro study did not show any effect of maternal use of ketanserin on the foetal 5HT2a receptors. . Due to the limited efficacy of ketanserin, nicardipine was studied as an alternative antihypertensive drug. In 27 pre-eclamptic patients, second-line treatment with intravenous nicardipine resulted in a fast and effective blood pressure lowering. However, in one third of the patients, unwanted hypotensive periods occurred, indicating that the dosage schedule needs to be further optimised. Placental transfer and transfer in breast milk was found to be low. In conclusion, intravenous ketanserin is found to result in insufficient antihypertensive response in severe pre-eclamptic patients. Nicardipine appears to be a potent alternative drug in the treatment of severe pre-eclampsia.

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