Antihistamines blood-brain barrier

The sedation side effect commonly observed on administration of classical antihistaminic drugs has been attributed in part to the ease with which many of these compounds cross the blood brain barrier. There have been developed recently a series of agoits, for example, terfenadine (198), which cause reduced sedation by virtue of decreased penetration into the CNS. This is achieved by making them more hydrophilic. Synthesis of a related compound, ebastine (197),... 

Demethylation of the tricyclic antihistamine 9, with cyanogen bromide gives the secondary amine 10 acylation of that intermediate with ethyl chloroformate affords the nonsedating H-1 antihistaminic agent loratidine (11) [3], It is of interest that this compound does not contain the zwitterionic funcrion which is thought to prevent passage through the blood-brain barrier, characteristic of this class of compounds. 

The belief that histamine (HT) has a central effect stems from the knowledge that all the classical antihistamines (Hi receptor antagonists) used to treat allergic reaction, such as hay fever, caused marked sedation if, like mepyramine and promethazine, they can cross the blood-brain barrier, but fail to do so if, like terfenedine and cetirizine, they do not. 

Pharmacy application antihistamines and the blood-brain barrier... 

The hypothesis of the role of HA in wakefulness stems from the observation that administration of the classical antihistamines (i.e. H3 receptor antagonists) induced sedation. These first-generation antihistamines, used to treat inflammatory reactions, could cross the blood-brain barrier and block the central Hi receptor (White Rumbold, 1988). The first study examining the effect of antihistamines on sleep-wakefulness in cats reported an increase in NREM sleep and a decrease in REM sleep (Jewett, 1968). Similar results were also obtained in dogs (Wauquier et ah, 1981) and humans (Risberg et ah, 1975 Bassano Caille, 1979 Nicholson et ah, 1985 Adam Oswald, 1986). Intraventricular application of HA in the anesthetized rat caused a dose-dependent decrease in the duration of narcosis, whereas intraventricular application of HA in conscious... 

The Hi-antagonists are classified as either first- or second-generation compounds. Second-generation antihistamines have lipophilicity and ionization profiles that make them less able to cross the blood-brain barrier thus they produce dramatically less sedation than do the first-generation drugs. 

The first generation Hi blockers (including diphenhydramine and hydroxyzine) cross the blood-brain barrier. Subsequent generations of antihistamines have been developed so that they do not cross the blood-brain barrier, and therefore are not effective as sedatives or anxiolytics. 

Fexofenadine inhibited antigen-induced bronchospasm and histamine release from mast cells. No anticholinergic or alpha adrenergic-receptor blocking effects were observed. Moreover, no sedative or other CNS effects were observed. Fexofenadine does not cross the blood-brain barrier. It inhibits skin wheal and flare responses produced by histamine injection. Following single and twice daily oral administration, antihistaminic effects occurred within 1 hour, achieved a maximum at 2-3 hours, and lasted a minimum of 12 hours. 

Considerable work has been devoted to the search for agents devoid of the sedative effect that accompanied some of the earlier antihistamines. One stratagem for achieving that comprises adding a function that will diminish the likelihood that the dmg will cross the blood-brain barrier. The antistamine emedastine (41-3), for example, incorporates a terminal ether that can be potentially metabolized to a carboxylic acid. Alkylation of the imidazole (41-1), available from imidazol-2-one by reaction with phosphoms oxychloride, with the chloroether (41-2) leads to a reaction on nitrogen to afford (41-3). Displacement of the enol chloride in that intermediate with A-methyl-l-4-diazepine (41-4) leads to emedastine (41- 5) [43]. 

The use of antihistamines can be traced back to the beginning of 1940s. The applications of the first-generation antihistamines were limited since they cause significant adverse effects such as sedation, memory impairment and psychomotor dysfunction. The second-generation antihistamines have significantly fewer central nervous system (CNS) adverse effects because they penetrate the blood-brain barrier much less extensively. 

Both prescription and over-the-counter antihistamines are the most commonly pre-scribed/recommended sedatives in pediatric practice. They bind to Hi receptors in the CNS, with only the first generation medications crossing the blood-brain barrier. They are generally rapidly absorbed. Effects on sleep architecture are minimal. Side effects include daytime drowsiness, cholinergic effects and paradoxical excitation. In general, these drugs are rather weak soporifics, but parental and provider familiarity tend to make them a more acceptable choice for many families. 

Q7 Fexofenadine is a metabolite of another antihistamine, terfenadine, but has little or no cardiac toxicity. The development of sedation and antimuscarinic effects are limited since fexofenadine cannot easily cross the blood-brain barrier (only a very small amount can cross this barrier). The recommended adult dosage is 120 mg once daily. It is also recommended for children above 12 years of age. 

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