PHARMACOKINETICS

The pharmacokinetic properties of various benzodiazepines are compared in Table 19–1. The benzodiazepines are absorbed from the gut and distributed to the brain at rates that are proportional to their lipid solubility, which varies 50-fold among individual drugs in the class. As the plasma concentration of a benzodiazepine declines, the drug is redistributed from the brain to the blood, and this mechanism contributes significantly to the termination of its effects on the CNS.

All benzodiazepines are extensively metabolized in the liver. Most benzodiazepines are converted to active metabolites in phase I oxidative reactions catalyzed by cytochrome P450 enzymes. The active metabolites of chlordiazepoxide, diazepam, and flurazepam are long acting and contribute to the long duration of action of these agents. The active metabolites of alprazolam, estazolam, midazolam, and triazolam are shorter acting. Each of these active metabolites is eventually conjugated with glucuronate to form an inactive polar metabolite that is excreted in the urine. Other drugs, namely oxazepam, temazepam, and lorazepam, bypass phase I oxidation and are metabolized only by phase II conjugation (Fig. 19–1). These three drugs may be safer for use by elderly patients, because the capacity to conjugate drugs does not decline with age as much as the capacity for oxidative biotransformation does. Hence, these three drugs are less likely to accumulate to toxic levels in elderly patients.

Figure 19–1 Major biotransformation pathways of benzodiazepines. Chlordiazepoxide and diazepam are converted to long-acting active metabolites. Alprazolam, midazolam, and triazolam are converted to a short-acting active metabolite. All benzodiazepines, including those with no active metabolites, are eventually converted to glucuronide compounds that are pharmacologically inactive and are excreted in the urine. The benzodiazepines that have no active metabolites include oxazepam, temazepam, and lorazepam (“out the liver”), and these may be the safest benzodiazepines to use in treating elderly patients.

Benzodiazepines also undergo some degree of enterohepatic cycling that prolongs their duration of action. In fact, some patients who are taking a drug such as diazepam may notice an increased sedative effect after eating a high-fat meal. The fatty meal causes the gallbladder to empty and thereby delivers bile containing diazepam to the intestines for reabsorption into the circulation.

MECHANISM OF ACTION

The benzodiazepines and barbiturates are believed to exert their effects on consciousness and sleep by facilitating the activity of γ-aminobutyric acid (GABA) at various sites in the neuraxis. GABA, the most ubiquitous inhibitory neurotransmitter in the CNS, regulates the excitability of neurons in almost every neuronal tract. As shown in Figure 19–2, the GABA_A receptor–chloride ion channel has binding sites for benzodiazepines and barbiturates, as well as alcohols, steroids, and inhalational anesthetics. This receptor–ion channel complex is made up of five subunits with the major form of the complex containing α, β, and γ subunits. However, there are at least 16 types of these protein subunits (e.g., α₁, α₂, β₁, β₂, etc.), and it is not entirely clear which types of subunits make up the GABA_A receptors that mediate the clinical and adverse effects of drugs that bind to them.

Figure 19–2 Receptor sites for GABA, benzodiazepines, barbiturates, and ethanol on the GABA_A chloride ion channel. The GABA_A chloride ion channel is a protein complex pentameric form that has varying combinations of α, β, and γ subunits. GABA binds to a site near the junction of α and β subunits, and this causes conformational changes that open the chloride ion channel and lead to neuronal membrane hyperpolarization. Benzodiazepines bind to an allosteric site formed by the cleft between α and γ subunits, and this facilitates GABA binding and increases the frequency of chloride channel opening. Barbiturates bind adjacent to α and β subunits and increase the duration of chloride channel opening, both in the presence and in the absence of GABA. Ethanol (ethyl alcohol) binds to a distinct site on the ionophore and enhances chloride influx. The ionophore also contains binding sites for steroids and inhalational anesthetics.

The benzodiazepine binding site is located at the interface between α and γ subunits at a site different than the binding site of GABA. Benzodiazepines bind to this site and increase the affinity of GABA for its binding site on the GABA_A receptor–chloride ion channel complex. This is an example of an allosteric binding site. Benzodiazepines bind to receptors made up of both α₁ and α₂ subunits, whereas the newer nonbenzodiazepine agents (see below) are selective for receptors containing α₁ subunits.

Benzodiazepines increase the frequency with which the channel opens, whereas barbiturates increase the length of time that the channel remains open. By increasing chloride conductance, these drugs cause neuronal membrane hyperpolarization and this, in turn, counteracts the depolarizing effect of excitatory neurotransmitters. Barbiturates increase chloride conductance independent of the presence of GABA, which is why they are capable of causing greater CNS depression and toxicity than the benzodiazepines.

In addition to their effects on GABA, benzodiazepines also inhibit the neuronal reuptake of adenosine. This action increases the inhibitory effect of adenosine on neurons that release acetylcholine from the pedunculopontine nucleus of the reticular formation, which is a brain structure mediating arousal. The effect of benzodiazepines on adenosine may also explain why these drugs dilate coronary arteries and decrease total peripheral resistance.