 Benzodiazepines (BZDs) are sedative-hypnotic agents

that were first introduced in 1960.

 BZDs commonly are used for a variety of situations
that include
1. seizure control
2. anxiety
3. alcohol withdrawal
4. insomnia
5. control of drug-associated agitation
6. muscle relaxants
7. preanesthetic agents.
8. They also are combined frequently with other
medications for procedural sedation.
 Because of their widespread use, these
drugs have propensity for abuse.
 In addition, benzodiazepines frequently
are used in overdose, either alone or in
association with other substances.
 Benzodiazepines (BZD) exert their action by
potentiating the activity of GABA. They bind
to a specific receptor on the GABA A receptor
complex, which facilitates the binding of
GABA to its specific receptor site.
 BZD binding causes increased frequency of
opening of the chloride channel complexed
with the GABA A receptor.
 Chloride channel opening results in
membrane hyperpolarization, which inhibits
cellular excitation.
 Enhanced GABA neurotransmission results in
sedation, striated muscle relaxation,
anxiolysis, and anticonvulsant effects.
 Stimulation of peripheral nervous system
GABA receptors may cause decreased cardiac
contractility and vasodilation. These changes
could have the potential to alter tissue
perfusion.
 Toxicity of Benzodiazepines

Classification of
benzodiazepines
Long-acting Intermediate – Short-acting
benzodiazepines acting benzodiazepine
1-3 days benzodiazepines 3-8 hours
16 hours hours
Clorazepate Alprazolam Oxazepam
Chlordiazepoxide Estazolam Triazolam
Diazepam Lorazepam
Flurazepam Temazepam
Quzepam
 BZDs are metabolized predominantly in the
liver by oxidation and/or conjugation.
 Most BZDs are broken down into
pharmacologically active metabolites, which
may have longer half-lives than the parent
compounds.
 The rate of BZD onset of action is determined by
its ability to cross the blood-brain barrier.
 The relatively lipophilic BZDs usually produce a
faster onset of effect than the relatively water-
soluble BZDs.
 BZD effects can be potentiated when ethanol is
present as coingestant.
 Peak blood concentrations of most agents occur
within 1-3 hours.
 After a single dose, the lipophilic agents can
have a shorter duration of action (shorter CNS
effect) than water-soluble agents because rapid
redistribution from the CNS to peripheral sites
(eg, adipose tissue); thus, lorazepam (water
soluble) has a longer CNS duration of action than
diazepam (lipophilic).
 However, diazepam metabolizes to active
intermediates with prolonged half-life extending
its therapeutic effects.
 Benzodiazepines generally are thought to be safe
and death is rare.
 Mortality and morbidity from a pure oral BZD
overdose is rare; it usually occurs in conjunction
with concomitant alcohol ingestion or use of
other sedative-hypnotics.
 Intravenous administration or overdose of
ultrashort-acting BZDs (eg, triazolam) is more
likely to result in apnea and death.
 Elderly individuals and very young persons are
more susceptible to the CNS depressant effects
of BZDs than people in other age groups.
 Intravenous administration is associated with
greater degrees of hypotension than other routes
of administration and occasional cardiac and
respiratory arrest.
 Toxicity of Benzodiazepines

• Benzodiazepines toxicity (cont’d):

- Psychological and physical dependence on
benzodiazepines can develop if high doses of
the drugs are given over a prolonged period.
- Abrupt discontinuation of the benzodiazepines
results in withdrawal symptoms, including
anxiety, agitation, restlessness, rebound
insomnia, tension, tremors and rarely,
seizures.
- Because of the long half-lives of some
benzodiazepines (e.g. Diazepam), withdrawal
symptoms may occur slowly and last a number
of days after discontinuation of therapy.
Benzodiazepines with a short elimination half-
life, such as triazolam, induce more abrupt
and severe withdrawal reactions than those
seen with drugs that are slowly eliminated,
such as flurazepam
 History should include the time, dose, and
intent of the overdose.
 Determine if co-ingestants are present and
the duration of benzodiazepine use.
 Signs and symptoms
1. Dizziness, Confusion,Drowsiness,
Unresponsiveness, Anxiety, and Agitation
2. Blurred vision and Nystagmus
3. Slurred speech, ataxia, Weakness
4. hypotension
5. Respiratory depression
6. Coma
Work up
- as barbiturates.
Management
 As barbiturates
 Flumazenil is a competitive BZD receptor
antagonist and should be used cautiously
because it has potential to precipitate BZD
withdrawal in chronic users, resulting in
seizures.
 Flumazenil administration is contraindicated
in mixed overdoses (eg, TCAs) because BZD
reversal can precipitate seizures and cardiac
arrhythmias.