Pharmacology

The parent compound, barbituric acid (2,4,6-trioxohexahydropyrimidine), itself has no central depressant activity. R-group substitutions primarily at position 5 give these compounds their sedative-hypnotic properties. Substituting a sulfur for the oxygen at position 2 creates a thiobarbiturate, which is more lipid soluble than an oxybarbiturate (Fig 157-1). High lipid solubility allows an agent to rapidly transit the blood-brain barrier and confers a shorter duration of action and greater degree of hypnotic activity.5 Traditionally, barbiturates have been classified according to their duration of action ( Table 1.5.7.-1.).

Long-acting barbiturates tend to be weaker acids (lower p Ka values), less lipid soluble, and less protein bound than shorter-acting barbiturates. This translates to a delayed onset of action, decreased volume of distribution, and longer duration of action when compared with short-, ultrashort-, and intermediate-acting compounds. Furthermore, tissue permeability of long-acting barbiturates is uniquely affected by body fluid pH changes. Only nonionized drug is membrane permeable. Phenobarbital has a p Ka of 7.24 and is 95 percent ionized at pH 7.4. Ionization will increase in a basic medium, and permeability will decrease. Conversely, an acidic medium will facilitate phenobarbital permeability by maintaining more drug in a nonionized state. This principle underpins the therapeutic usefulness of alkaline diuresis in long-acting barbiturates overdose.

Short-, ultrashort-, and intermediate-acting barbiturates are not affected by body pH changes. Secobarbital, for example, has a p Ka of 7.9 and is 98 percent nonionized at pH 7.4. Rate of barbiturate delivery to the membrane determines tissue permeability with these classes. These compounds are stronger acids (higher pKa values), more lipid soluble, and more protein bound, enabling a more rapid onset of action, greater volume of distribution, and shorter duration of action compared with the long-acting barbiturates.5

Bulk absorption of barbiturates occurs in the stomach and small intestine, where most of the drug exists in a nonionized state. Overall, barbiturates readily diffuse into the body tissues and cross the blood-brain barrier, with highest concentrations occurring in the brain, liver, kidney, and adipose tissue. Barbiturates are excreted in breast milk and easily cross the placenta. Fetal blood barbiturate concentrations closely reflect maternal plasma levels. 4 Interestingly, in utero exposure to phenobarbital has been significantly linked to verbal intelligence deficits in adult men. 8 Tolerance develops with chronic barbiturate use, and higher doses are required to produce the same effects. Most barbiturates are metabolized by the liver to inactive by-products. Hepatic biotransformation occurs primarily through routes involving the cytochrome P-450 microsomal enzyme system. All barbiturates are capable of inducing the activity of this enzyme system. Increased rates of metabolism for many drugs, including oral contraceptives, anticoagulants, and corticosteroids, have been observed in patients with chronic barbiturate use. Depending on the degree of hepatic biotransformation, variable amounts of barbiturates are excreted unchanged in the urine. Barbital and phenobarbital are less protein bound and thus most dependent on the renal excretion pathway.9 Elimination half-life of barbiturates can be greatly accelerated in infants and children and very prolonged in the elderly and in patients with liver or renal disease.45

The main action of barbiturates is to depress activity in nerve and muscle tissues. In the central nervous system (CNS) this is accomplished by enhancing the action of the primary inhibitory neurotransmitter g-aminobutyric acid (GABA) at the postsynaptic membrane. Additionally, barbiturates may act by inhibiting calcium-mediated excitatory neurotransmitter release at the presynaptic junction.li5

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