ABSTRACT
As a class, barbiturates are largely nonionic, lipid-soluble compounds, and their pKa ranges between 7.2 and 7.9. The dissociation constants, therefore, do not account for differences in duration of action, especially with the long-acting compounds. Rapid movement into and out of the CNS appears to determine rapid onset and short duration. Conversely, the barbiturates with the slowest onset and longest duration of action contain the most polar side chains (ethyl and phenyl with phenobarbital structure, Table 13.1). Thus, the structure in Table 13.1 dictates that phenobarbital enters and leaves the CNS very slowly compared with the more lipophilic thiopental (with intermediate pKa). In addition, the lipid barriers to drug-metabolizing enzymes lead to a slower metabolism for the more polar barbiturates, considering that phenobarbital is metabolized to the extent of 10% per day. Similarly, distribution in biological compartments, especially the CNS, is governed by lipid solubility.
