Lipophilicity, Hydrophilicity, and the Central Nervous System Side Effects of Beta Blockers

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Abstract
One of the attributes of beta‐adrenergic blocking agents that has distinguished these drugs from each other is degree of lipophilicity. While this feature may play a role in facilitating passage across the blood‐brain barrier, it is essential to realize that crossing the barrier is not necessarily synonymous with the ability to cause central nervous system (CNS) effects. Several studies have found some degree of CNS side effects, particularly tiredness and fatigue, with atenolol, a hydrophilic beta blocker. Pindolol, a moderately lipophilic beta blocker, has been reported to cause greater disturbances on electroencephalogram (EEG) than propranolol, the most highly lipophilic beta blocker. The investigational agent bevantolol exhibits a moderate degree of lipophilicity and a low frequency of CNS side effects. Drug‐induced increases in plasma catecholamine levels, the possible saturation of CNS receptor sites at relatively low drug levels, and the specific structural details of beta‐blocker molecules have been suggested as possible contributory factors in determining the degree of CNS effects.