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Benzodiazepine Pharmacokinetics

The pharmacokinetic properties of a drug determine its onset of action and the duration of its effect. Specifically, pharmacokinetics describes the absorption, distribution, metabolism, and excretion of a drug (ie, what the body does to the drug). Pharmacodynamics describes the responsiveness of receptors to a drug and the mechanism by which these effects occur (ie, what the drug does to the body). Individuals respond differently to the same drug, and often these different responses reflect the pharmacokinetics and/or pharmacodynamics among different patients.

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Pharmacokinetics (determination of the onset of action and the duration of drug effect) is affected by route of administration, absorption, and volume of distribution. BZDs can be administered via intramuscular, intravenous, oral, sublingual, intranasal, or rectal gel forms. Characteristics of the drug—including lipid solubility, binding to plasma proteins, and molecular size—influence the volume of distribution. Pharmacodynamics and pharmacologic drug effects are described in terms of dose-response curves that depict the relationship between the dose and the resulting pharmacologic effect. Dose-response curves predict the effect of the drug on the patient as doses increase. Titration of a drug should proceed based on the expected pharmacodynamics. Key considerations during titration of medications include making the appropriate choice for the patient’s condition (eg, renal failure, liver failure, previous drug exposure), appropriate choice of incremental dosing (ie, time and quantity), and periodic monitoring.9

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Preexisting disease processes and age-related changes affect elimination half-life, an especially important consideration when administering BZDs. Elimination half-life is the time necessary for plasma concentration of a drug to decrease to 50% during the elimination phase. Because elimination half-life is directly proportional to the volume of distribution and inversely proportional to its clearance, renal and hepatic disease (altered volume of distribution and/or clearance) affect elimination half-life.

Elimination half-life does not reflect time to recovery from drug effects. Elimination half-life is an estimate of the time needed to reduce the drug concentration in the plasma by half. After about 5 elimination half-lives, a drug is nearly totally eliminated from the body. Therefore, drug accumulation is likely if dosing intervals are less than this period of time.

From a pharmacological perspective, BZDs are usually well absorbed by the gastrointestinal tract after oral administration. After intravenous administration, BZDs quickly distribute to the brain and central nervous system. BZD activity is terminated by redistribution similar to that of the lipid-soluble barbiturates. Following intramuscular injection, absorption of diazepam or chlordiazepoxide is slow and erratic, whereas absorption of intramuscular administration of lorazepam or midazolam appears to be rapid and complete. Lorazepam is well absorbed after sublingual administration, reaching peak levels in 60 minutes.2

BZDs and their metabolites are highly protein bound. They are widely distributed in the body and preferentially accumulate in lipid-rich areas such as the central nervous system and adipose tissue. As previously mentioned, the more lipophilic agents generally have the highest rates of absorption and fastest onset of clinical effects. Most BZDs are oxidatively metabolized by the cytochrome P450 enzymes (phase I), conjugated with glucuronide (phase II), and excreted almost entirely in the urine.

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Some BZDs exert additional action via production of active metabolites, an important consideration when prescribing these agents. Midazolam, one of the short-acting BZDs, produces no active metabolites. However, diazepam, a long-acting BZD, produces the active metabolites oxazepam, desmethyldiazepam, and temazepam; these metabolites further increase the duration of drug action and should be a serious consideration in some patient groups, especially the elderly and those with extensive hepatic disease.2

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