1.

Mechanism of action: Benzodiazepine, Z drugs,

Barbiturate
 ALL THREE bind to molecular components of the GABAA receptor in neuronal membranes in the CNS. This receptor, which functions as a
chloride ion channel, is activated by the inhibitory neurotransmitter GABA. In contrast to benzodiazepine, barbiturates appear to increase the
duration of the GABA-gated chloride channel openings.
2. Pharmacokinetics of benzodiazepine
A. Absorption and Distribution
 The rates of oral absorption of sedative-hypnotics differ depending on a number of factors, including lipophilicity. For example, the absorption of
triazolam is extremely rapid, and that of diazepam and the active metabolite of clorazepate is more rapid than other commonly used benzodiazepines.
Clorazepate, a prodrug, is converted to its active form, desmethyldiazepam (nordiazepam), by acid hydrolysis in the stomach. Most of the barbiturates and
other older sedative-hypnotics, as well as the newer hypnotics (eszopiclone, zaleplon, zolpidem), are absorbed rapidly into the blood following oral
administration. Lipid solubility plays a major role in determining the rate at which a particular sedative-hypnotic enters the CNS. This property is
responsible for the rapid onset of the effects of triazolam, thiopental, and the newer hypnotics. All sedative-hypnotics cross the placental barrier during
pregnancy. If sedative-hypnotics are given during the predelivery period, they may contribute to the depression of neonatal vital functions. Sedative-
hypnotics are also detectable in breast milk and may exert depressant effects in the nursing infant.

3. Adverse effects of Z drugs

 Adverse effects of zolpidem: Include nightmares, agitation, anterograde amnesia, headache, GI upset, dizziness, and daytime drowsiness.
 Adverse events with eszopiclone: include anxiety, dry mouth, headache, peripheral edema, somnolence, and unpleasant taste
 Adverse effects of Zaleplon: headache, dizziness, nausea, abdominal pain, weakness, dysmenorrhea, eye pain, amnesia, paresthesia, tremor
 4. TABULATED FORM

SEDATIVE-HYPNOTICS
CLASS OF DRUGS MOA CLINICAL PHARMACOKINETICS TOXICITIES DRUG
APPLICATION INTERACTION
BENZODIAZEPINE Benzodiazepines Reduction of anxiety, Absorption and Drowsiness and Alcohol and other
increase the frequency Sedative/hypnotic, distribution: The confusion are the most CNS depressants
of GABA-mediated Anterograde amnesia, benzodiazepines are common side effects of enhance the
chloride ion channel Anticonvulsant, Muscle lipophilic. They are rapidly the benzodiazepines. sedative–hypnotic
opening. relaxant. and completely absorbed Ataxia occurs at high effects of the
Benzodiazepines are after oral administration, doses and precludes benzodiazepines.
favored in the drug distribute throughout the activities that require a drug overdose is
treatment of acute body and penetrate into fine motor seldom lethal unless
anxiety states and for the CNS coordination, such as other central
rapid control of panic Duration of action: The driving an automobile. depressants, such as
attacks. half-lives of the Cognitive impairment alcohol, are taken
Benzodiazepines, benzodiazepines are (decreased long-term concurrently.
including estazolam, important clinically, recall and retention of
flurazepam, and because the duration of new knowledge) can
triazolam, have been action may determine the occur with use of
widely used in primary therapeutic usefulness. benzodiazepines.
insomnia and for the The benzodiazepines can Triazolam often shows a
management of certain be roughly divided into rapid development of
other sleep disorders. short-, intermediate-, and tolerance, early
certain benzodiazepines long-acting groups. The morning insomnia, and
(eg, diazepam, longer-acting agents form daytime anxiety, as well
midazolam) are used as active metabolites with as amnesia and
components of long half-lives. However, confusion.
anesthesia protocols with some
including those used in benzodiazepines, the
day surgery clinical duration of action
does not correlate with the
actual half-life (otherwise,
a dose of diazepam could
conceivably be given only
every other day, given its
active metabolites). This
may be due to receptor
dissociation rates in the
CNS and subsequent
redistribution to fatty
tissues and other areas.
Fate: Most
benzodiazepines, including
chlordiazepoxide and
diazepam, are metabolized
by the hepatic microsomal
system to compounds that
 are also active. For these
benzodiazepines, the
apparent half-life of the
drug represents the
combined actions of the
parent drug and its
metabolites. Drug effects
are terminated not only by
excretion but also by
redistribution. The
benzodiazepines are
excreted in the urine as
glucuronides or oxidized
metabolites. All
benzodiazepines cross the
placenta and may depress
the CNS of the newborn if
given before birth. The
benzodiazepines are not
recommended for use
during pregnancy. Nursing
infants may also be
exposed to the drugs in
breast milk.
BARBITURATE Barbiturates depress Depression of CNS, Barbiturates are well Barbiturates cause
neuronal activity in Respiratory depression, absorbed after oral drowsiness, impaired
the midbrain reticular clinical use: Anesthesia, administration and concentration, and
formation, facilitating Anticonvulsant, distribute throughout the mental and physical
and prolonging the Sedative/hypnotic. body. All barbiturates sluggishness. The CNS
inhibitory effects of Barbiturates are redistribute from the brain depressant effects of
GABA and glycine. classified according to to the splanchnic areas, to barbiturates synergize
Barbiturates also bind their duration of action. skeletal muscle, and, with those of ethanol.
to multiple isoforms of For example, ultra– finally, to adipose tissue.
the GABAA receptor short-acting thiopental This movement is
but at different sites [thye-ohPEN-tal] acts important in causing the
from those with which within seconds and has a short duration of action of
benzodiazepines duration of action of thiopental and similar
interact. about 30 minutes. In short-acting derivatives.
contrast, long-acting Barbiturates readily cross
phenobarbital [fee-noe- the placenta and can
 BAR-bital] has a duration depress the fetus. These
of action greater than a agents are metabolized in
day. Pentobarbital the liver, and inactive
[pentoe-BAR-bi-tal], metabolites are excreted
secobarbital [see-koe- in urine.
BAR-bi-tal], amobarbital
[am-oh-BAR-bi-tal], and
butalbital [bu-TAL-bi-tal]
are short-acting
barbiturates.
Z DRUGS In contrast to Zolpidem provides a Zolpidem has no
benzodiazepines, hypnotic effect. anticonvulsant or muscle-
these drugs bind more Zaleplon is similar in relaxing properties. It
selectively, interacting action with Zolpidem shows few withdrawal
only with GABAA effects, exhibits minimal
receptor isoforms that rebound insomnia, and
contain α1 subunits. little tolerance occurs with
prolonged use.
zaleplon causes fewer
residual effects on
psychomotor and cognitive
function compared to
zolpidem or the
benzodiazepines. This may
be due to its rapid
elimination, with a half-life
of approximately 1 hour.
The drug is metabolized by
CYP3A4.
Eszopiclone is rapidly
absorbed (time to peak, 1
hour), extensively
metabolized by oxidation
and demethylation via the
CYP450 system, and mainly
excreted in urine.
Elimination half-life is
approximately 6 hours.