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222 Psychopharmacologicals

Benzodiazepines

Balanced CNS activity requires inhibitory and excitatory mechanisms. Spinal and cerebral inhibitory interneurons chiefly utilize γ-aminobutyric acid (GABA) as transmitter substance, which decreases the excitability of target cells via GABAA receptors. Binding of GABA to the receptor leads to opening of a chloride (Cl)ion channel, chloride influx, neuronal hyperpolarization, and decreased excitability. The pentameric subunit assembly making up the receptor/ion channel contains a high-af nity binding site for benzodiazepines, in addition to the GABA binding locus. Binding of benzodiazepine agonists allosterically enhances binding of GABA and its action on the channel. The prototypical benzodiazepine is diazepam. Barbiturates also possess an allosteric binding site on the Cl-channel protein; their effect is to increase the channel mean open-time during GABA stimulation.

Benzodiazepinesexhibit a broad spectrum of activity: they exert sedating, sleep-induc- ing, anxiolytic, myorelaxant, and anticonvulsant effects and can be used for induction of anesthesia. Of special significance for the use of benzodiazepines is their wide margin of safety. At therapeutic dosages, neither central respiratory control nor cardiovascular regulation are affected. By virtue of these favorable properties, benzodiazepines have proved themselves for a variety of indications. At low dosage, they calm restless or agitated patients and allay anxiety, though without solving problems. Use of benzodiazepines as sleep remedies is widespread. Here, preference is given to substances that are completely eliminated during the night hours (tetracyclic compounds such as triazolam, brotizolam, alprazolam). For longerlasting anxiolytic therapy, compounds should be selected that are eliminated slowly and ensure a constant blood level (e.g., diazepam).

In psychosomatic reactions, benzodiazepines can exert an uncoupling effect. They

are therefore of great value in hyperacute disease states (e.g., myocardial infarction, p.320) or severe accidents. Status epilepticus is a necessary indication for parenteral administration (p.190); however, benzodiazepines can also be used for the long-term treatment of certain forms of epilepsy, if necessary in combination with other anticonvulsants. Rapidlyeliminatedbenzodiazepines are suitable for the intravenous induction of anesthesia.

Use of benzodiazepines may lead to personality changes characterized by flattening of affect. Subjects behave with indifference andfailto reactadequately. Anytasksrequiring prompt and target-directed action—not only driving a motor vehicle—should be left undone.

Benzodiazepine Antagonist

The drug flumazenil bindswith high af nity to the benzodiazepine receptor but lacksany agonist activity. Consequently, the receptor is occupied and unavailable for binding of benzodiazepine agonists. Flumazenil is a specific antidote and is used with success for reversal of benzodiazepine toxicity or to terminate benzodiazepine sedation. When patients suffering from benzodiazepine dependence are given flumazenil, withdrawal symptoms are precipitated.

Flumazenil is eliminated relatively rapidly with a t½ of ~ 1 hour. Therefore, the required dose of 0.2–1.0 mg i.v. must be repeated a corresponding number of times when toxicity is due to long-acting benzodiazepines.

Luellmann, Color Atlas of Pharmacology © 2005 Thieme

All rights reserved. Usage subject to terms and conditions of license.

 

Benzodiazepines

223

A. Action of benzodiazepines

 

 

 

GABAergic

 

neuron

 

Benzo-

 

GABA

diazepine

Cl-

binding

binding site

site

 

α

β

Barbiturate

binding site

β

α

 

 

γ

 

Anxiolyis

 

 

 

 

Plasma-

 

 

lemma

 

Cl-

 

 

GABA

Binding site for

 

binding

Benzodiazepines

 

site

Barbiturates

 

 

 

Positive allosteric modulators of GABA effect increase

 

in Cl- conductance hyperpolarization

 

decreased excitability

 

Plus anticonvulsant effect,

GABAA receptor

 

sedation, muscle relaxation

with allosteric binding sites

 

 

 

 

 

Benzodiazepines

 

CH3

 

 

 

 

CH2

 

 

 

 

O

 

 

 

O

C

CH3

 

 

 

 

 

 

N

 

N

 

 

 

N

O

 

 

 

 

 

 

 

 

F

 

 

Flumazenil

 

Normal

Enhanced

Benzodiazepine antagonist

GABAergic inhibition

GABAergic inhibition

Luellmann, Color Atlas of Pharmacology © 2005 Thieme

All rights reserved. Usage subject to terms and conditions of license.

224 Psychopharmacologicals

Pharmacokinetics of Benzodiazepines

A typical metabolic pathway for benzodiazepines, as exemplified by the drug diazepam, is shown in panel (A): first the methyl group on the nitrogen atom at position 1 is removed, with a concomitant or subsequent hydroxylation of the carbon at position 3. The resulting product is the drug oxazepam. These intermediary metabolites are biologically active. Only after the hydroxyl group (position 3) has been conjugated to glucuronic acid is the substance rendered inactive and, as a hydrophilic molecule, readily excreted renally. The metabolic degradation of desmethyldiazepam (nordiazepam) is the slowest step (t½ = 30–100 hours). This sequence of metabolites encompasses other benzodiazepines that may be considered precursors of desmethyldiazepam, e.g., prazepam and chlordiazepoxide (the first benzodiazepine = Librium ). A similar metabolite pattern is seen in benzodiazepines in which an NO2 group replaces the chlorine atom on the phenyl ring and in which the phenyl substituent on carbon 5 carries a fluorine atom (e.g., flurazepam). With the exception of oxazepam, all these substances are long-acting. Oxazepam represents those benzodiazepines that are inactivated in a single metabolic step; nevertheless, its half-life is still as long as 8 ± 2 hours. Substances with a short half-life result only from introduction of an additional nitrogen-con- taining ring (see A) bearing a methyl group that can be rapidly hydroxylated. Midazolam, brotizolam, and triazolam are members of such tetracyclic benzodiazepines; the latter two are used as hypnotics, whereas midazolam given intravenously is employed for anesthesia induction.

Another possible way of obtaining compounds with an intermediate duration of action is to replace the chlorine atom in diazepam with an NO2 residue (rapidly reduced to an amine group with immediate acetylation) or with a bromine atom (which

causes ring cleavage in the organism). In these cases, biological inactivation again consists of a one-step reaction.

Dependence potential. Prolonged regular use of benzodiazepines can lead to physical dependence. With the long-acting substances marketed initially, this problem was less obvious in comparison with other depen- dence-producing drugs, because of the delayed appearance of withdrawal symptoms (the decisive criterion for dependence). Symptoms manifested during withdrawal include restlessness, irritability, nervousness, anxiety, insomnia, and, occasionally or in susceptible patients, convulsions. These symptoms are hardly distinguishable from those considered indications for the use of benzodiazepines. Benzodiazepine withdrawal reactions are more likely to occur after abrupt cessation of prolonged or excessive dosage and are more pronounced in shorter-acting substances, but may also be evident after discontinuance of therapeutic dosages administered for no longer than 1–2 weeks.

Administration of a benzodiazepine antagonist would abruptly provoke abstinence signs. Benzodiazepines exhibit cross-de- pendence with ethanol and can thus be used in the management of delirium tremens. There are indications that substances with intermediate elimination half-lives have the highest abuse potential. Withdrawal of benzodiazepines should be done gradually and cautiously. A long-acting substance such as diazepam is the drug of choice for controlled tapering of withdrawal.

Luellmann, Color Atlas of Pharmacology © 2005 Thieme

All rights reserved. Usage subject to terms and conditions of license.

Pharmacokinetics of Benzodiazepines

225

A. Biotransformation of benzodiazepines

H3C

Midazolam

 

 

Diazepam

H3C

 

 

N

 

 

 

 

 

 

 

N1

O

 

 

 

 

 

 

 

 

 

 

 

N

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

3

Cl

N

 

 

 

 

 

 

Cl

5

N

 

 

F

 

 

 

 

 

 

 

 

 

 

HOH2C

N

 

 

 

 

 

 

 

H

O

 

N

 

 

 

 

 

 

 

 

N

 

 

 

 

 

 

 

 

 

 

 

 

 

 

OH

 

as glucuronide

 

 

H

O

 

N

 

 

N

 

 

 

 

 

 

 

 

 

H

O

N

 

 

 

 

 

 

 

 

 

 

OH

 

 

 

 

 

 

 

 

N

 

 

 

 

 

 

 

 

 

 

 

N

 

 

 

 

 

 

 

 

 

 

O

 

 

 

 

Inactive

 

 

 

 

 

 

 

 

 

 

 

 

 

N

 

Nordiazepam

 

 

 

 

 

 

 

Gluc

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Oxazepam

 

 

 

 

 

 

 

 

 

 

Active metabolites

 

B. Rate of elimination of benzodiazepines

 

 

 

 

 

 

 

 

 

 

i.v. induction of anesthesia

 

 

Midazolam

 

 

 

 

 

 

 

Hypnagogic effect

Triazolam

 

 

 

 

 

 

 

 

 

 

Brotizolam

 

 

 

 

 

 

 

 

 

 

Oxazepam

 

 

 

 

 

 

 

 

 

 

Lormetazepam

 

 

 

 

 

 

 

 

 

Bromazepam

 

 

 

 

 

 

 

 

 

Flunitrazepam

 

 

 

 

 

 

 

 

 

Lorazepam

 

 

 

 

 

 

 

 

 

 

Camazepam

 

 

 

 

 

 

 

 

 

Nitrazepam

 

 

 

 

 

 

 

 

 

Clonazepam

 

 

 

 

 

 

 

 

 

Diazepam

 

 

 

Precursor

 

 

 

 

 

Temazepam

 

 

 

 

 

 

Anxiolysis

Prazepam

 

 

 

 

 

 

 

 

 

 

 

 

0

10

20

30

40

 

50

60

 

>60 hours

 

Range of plasma t1/2

 

Applied drug

 

Active metabolite

 

 

 

 

Luellmann, Color Atlas of Pharmacology © 2005 Thieme

All rights reserved. Usage subject to terms and conditions of license.

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