Quantification of Bisoprolol and Metoprolol in Simultaneous Human Serum and Cerebrospinal Fluid Samples

Abstract

Background: Bisoprolol and metoprolol are moderately lipophilic, beta(1)-selective betablockers reported to cause adverse effects in the central nervous system (CNS), such as sleep disturbance, suggesting that both drugs may reach relevant concentrations in the brain. CNS beta(2)-receptor blockade has been suspected to be related to such effects. The higher molecular size of bisoprolol (325 Dalton) and the higher beta(1)-selectivity compared to metoprolol (267 Dalton) would suggest a lower rate of CNS effects. Methods: To address the pharmacokinetic background of this assumption, we quantified to which extent these beta(1)-blockers are able to enter the cerebrospinal fluid (CSF) in 9 (bisoprolol group) and 10 (metoprolol group) neurological patients who had received one of the drugs orally for therapeutic purposes prior to lumbar puncture. We quantified their total concentrations by liquid chromatography/tandem mass spectrometry in paired serum and CSF samples. Results: Median (interquartile range) in CSF reached 55% (47-64%) of total serum concentrations for bisoprolol and 43% (27-81%) for metoprolol, corresponding to 78% (67-92%) and 48% (30-91%) of respective unbound serum concentrations. Conclusion: The extent of penetration of bisoprolol and metoprolol into the CSF is similar and compatible with the assumption that both drugs may exert direct effects in the CNS.

Factors associated with the severity of delirium

“…In the present study, patients receiving carvedilol (40%) and/or bisoprolol (56%) accounted for over 95% of patients receiving β-blockers. There are few reports of the associations between these newer β-blockers and delirium (Aikoye et al, 2019;Shigaroudi et al, 2018). The result of the present study may support the above guidelines and the hypothesis that β-blockers may be useful adjuncts for managing delirium.…”

“…It is known that β-blockers, especially the very lipophilic agents such as propranolol, are associated with the development of delirium (Alagiakrishnan & Wiens, 2004). However, although lipophilicity is considered to be one of the factors that affect the central nervous system (CNS), other drug-specific factors may affect the CNS (Shigaroudi et al, 2018). For example, penetration of the CNS by atenolol is limited because of its hydrophilic nature; therefore, its untoward effects on the CNS should be fewer compared with other β-blockers, but it has been reported that atenolol at high doses may cause organic brain syndrome (Arber, 1988).…”

Bisoprolol, Known to Be a Selective β1-Receptor Antagonist, Differentially but Directly Suppresses IK(M) and IK(erg) in Pituitary Cells and Hippocampal Neurons

“…Bisoprolol (zebeta ® ; BIS), a phenoxy-2-propanol derivative, is recognized as an oral synthetic selective blocker of β 1 -adrenoceptor with antioxidant activity which exerts a number of potentially beneficial pharmacological effects such as atrial fibrillation, heart failure and postural tachycardia syndrome [1,2,3,4]. Due to its lipophilic nature, it facilitates entry into brain tissue to produce regulatory actions on central neurons [5,6]. Previous reports have demonstrated that BIS could bind to β 1 -adrenergic receptors inherently existing in brain areas including the pituitary gland and hippocampus [7,8,9,10,11].…”

The association between beta-blocker therapy and daytime sleepiness in obstructive sleep apnoea

“…Data are presented as median and interquartile range patients who took bisoprolol. Bisoprolol is a moderately lipophilic drug that penetrates the brain, and its concentrations in the cerebrospinal fluid are comparable to those in plasma [5]. In contrast to other beta-blockers such as carvedilol or labetalol, it may also influence the production of melatonin which is a key regulator hormone of human sleep and circadian rhythm [18][19][20].…”

“…In particular, sleep-related side effects include drowsiness, sleepiness, fatigue, nightmares and other parasomnias [3,4]. Lipophilic drugs such as propranolol, metoprolol or betaxolol can enter CNS and achieve high concentration in the cerebrospinal fluid, while moderately lipophilic beta-blockers such as bisoprolol, nebivolol or carvedilol only partly penetrate through the blood-brain barrier [5]. In contrast, hydrophilic drugs such as sotalol or atenolol have a weak passage with poor distribution in CNS [6].…”