Sedative-Hypnotics
CMHS, Department of Pharmacy; Pharmacology unit
Introduction
• Sedative (anxiolytic): A drug that reduce anxiety and
calms the subject without inducing sleep.
• Hypnotic: A drug that induces and/or maintains sleep,
similar to normal arousable sleep.
• Hypnotic effects involve more pronounced depression of
the CNS than sedation.
Introduction …
 ↑ing grades of CNS depression.
– Sedation
Hypnosis
General
anaesthesia
• Treatment of insomnia is the most important
use of this class of drugs.
Classification
1. Barbiturates
Classification…
2. Benzodiazepines(BZDs)
Note: A substituent in the 7 position, such as a halogen or
a nitro group, is required for sedative-hypnotic
activity
Classification…
3. Newer non-BZD hypnotics
• Structurally unrelated to BZDs, share a
similar mechanism of action
Zopiclone,
eszopiclone
Zolpidem,
zaleplon
and
Pharmacokinetics
• The rates of oral absorption of sedative-hypnotics
differ depending on a # of factors, including
lipophilicity.
 For instance:
– Triazolam is extremely rapidly absorbed
– Diazepam and clorazepate (its active metabolite) is
more rapidly absorbed than other commonly used
BZDs.
Pharmacokinetics…
• Most of the barbiturates and newer hypnotics: exhibit a
rapid absorbtion.
• CNS penetration of a given sedative-hypnotic is
determined by lipid solubility.
• This property is responsible for the rapid onset of the
effects of triazolam, thiopental and the newer hypnotics
Pharmacokinetics …
• All sedative-hypnotics cross the placental barrier during
pregnancy.
– They may depress neonatal vital functions(if given during
predelivery period).
• Are detectable in breast milk and may exert
depressant effects in the nursing infant
Pharmacokinetics …
• All BZDs are metabolized in the liver by cytochrome
P450 isozymes especially CYP3A4.
• The patterns and rates of metabolism depend on
the individual drugs.
• Many
phase
I
metabolites
of
BZDs
are
pharmacologically active
– E.g. Desmethyldiazepam:is an active metabolite of
chlordiazepoxide, diazepam, prazepam, and clorazepate
• Has a long elimination t1/2(> 40 hrs)
Fig :Biotransformation of BZDs
.
Pharmacokinetics …
• Only insignificant quantities of the barbiturates are
excreted unchanged except for phenobarbital.
• The overall rate of hepatic metabolism depends on the
individual drug
• Yet, its usually slow(except for thiobarbiturates).
• Sedative-hypnotics are excreted mainly via the kidney
Pharmacokinetics …
• Barbiturates
(especially
phenobarbital)
and
meprobamate on a long-term basis causes
enzyme induction.
• Result in an ↑ in their hepatic metabolism as
well as that of other drugs
• In contrast, BZDs and the newer hypnotics didn’t
causes such effect.
Mechanisms of action
• Both promote the effectiveness
of GABA receptors in the CNS.
• BZDs ↑ frequency and
barbiturates ↑ duration of
GABA mediated Cl- channel
opening.
• Barbiturates(At high conc) may
also be GABA-mimetic, directly
activating Cl- channels.
Mechanisms of action…
• Barbiturates are less selective in their actions
than benzodiazepines
• Also inhibit glutamate neurotransmission and exert
non-synaptic membrane effects (multiplicity of
sites of action) as result:
– They have an ability to induce full surgical anesthesia
– More pronounced central depressant effects
compared with BZDs and the newer hypnotics.
Organ Level Effects
1. Sedation
• Exert calming effects with concomitant
anxiolytic actions at relatively low doses.
• Accompanied by some depressant effects
on psychomotor and cognitive functions.
Organ Level Effects…
2. Hypnosis
• By definition, all of the sedative-hypnotics induce
sleep if high enough doses are given.
• The effects of sedative-hypnotics on the stages of
sleep depend on several factors including
– the specific drug, the dose, and the frequency of its administration.
Organ Level Effects…
• The general effects of BZDs and older sedative-hypnotics on
patterns of normal sleep are as follows:
1. The latency of sleep onset is decreased (time to fall asleep)
2. The duration of stage 2NREM (non-rapid eye movement)
sleep is increased
3. The duration of REM (rapid eye movement) sleep is
decreased
4. The duration of stage 4 NREM slow-wave sleep is decreased
Organ Level Effects…
• The newer hypnotics all decrease the latency to
persistent sleep.
e.g. Zolpidem decreases REM sleep but has minimal
effect on slow-wave sleep.
• More rapid onset of sleep and prolongation of
stage 2 are presumably clinically useful effects.
Organ Level Effects…
3. Anesthesia
• High doses of certain sedative-hypnotics depress the
CNS to the point known as stage III of general
anesthesia.
• However, the suitability of a particular agent as an
adjunct in anesthesia depends mainly on its
physicochemical properties
– Determining its rapidity of onset and duration of effect.
Organ Level Effects…
• Thiopental and methohexital are very lipid-soluble,
penetrating brain tissue rapidly f/f IV administration
– A characteristic favoring their use for the induction of
anesthesia.
• Rapid tissue redistribution accounts for the short
duration of action of these drugs
– A feature useful in recovery from anesthesia.
Organ Level Effects…
4. Anticonvulsant effects
• BZDs including clonazepam, lorazepam, and
diazepam are clinically useful in the
management of seizures.
• Barbiturates: phenobarbital and metharbital are
effective in the treatment of generalized tonicclonic seizures.
• However, zolpidem, zaleplon, and eszopiclone
lack anticonvulsant activity
Organ Level Effects…
5. Muscle relaxation
• Members of the carbamate (eg, meprobamate)
and BZD groups;
– Exert inhibitory effects on polysynaptic reflexes and
internuncial transmission
– Depress transmission at the skeletal neuromuscular
junction(at high doses)
Organ Level Effects…
• Useful for relaxing contracted voluntary
muscle in muscle spasm
• Muscle relaxation is not a characteristic
action of newer sedative –hypnotics.
Organ Level Effects…
6. Effects on respiration and cardiovascular
function
• At therapeutic doses, they can produce significant
respiratory depression in pts with pulmonary disease.
• Effects on respiration are dose-related
• Depression of the medullary respiratory center is the
usual cause of death due to overdose of sedativehypnotics.
Organ Level Effects…
• At doses up to those causing hypnosis
– No significant effects on the cardiovascular
system are observed in healthy pts.
• Normal doses of sedative-hypnotics may
cause cardiovascular depression.
– In hypovolemic states, heart failure, and other
diseases that impair cardiovascular function
Organ Level Effects…
• At toxic doses, myocardial contractility and
vascular tone may both be depressed
• Respiratory and cardiovascular effects are more
marked
when
intravenously
sedative-hypnotics
are
given
Flumazenil
• Has high affinity for the BZD binding site on the
GABAA receptor
– act as competitive antagonists
• It blocks many of the actions of BZDs, zolpidem,
zaleplon, and eszopiclone
• It does not antagonize the CNS effects of other
sedative-hypnotics, ethanol, opioids, or general
anesthetics.
Flumazenil…
Use
To reverse the CNS depressant effects of BZD
overdose
To hasten recovery following use of these
drugs in anesthetic and diagnostic procedures
Flumazenil…
• Has a short half-life (0.7–1.3 hours) due to rapid
hepatic clearance.
• Because all BZDs have a longer duration of
action than flumazenil
– Sedation commonly recurs, requiring repeated
administration of the antagonist.
• Adverse effects; agitation, confusion, dizziness,
and nausea.
Clinical uses of sedative-hypnotics
• For relief of anxiety
• For insomnia
• For sedation and amnesia before and during medical and
surgical procedures
• As a component of balanced anesthesia (IV administration)
• For control of ethanol or other sedative-hypnotic withdrawal
states
• For muscle relaxation in specific neuromuscular disorders
• Psychiatric uses
Tolerance
• Is a common feature of sedative-hypnotic use
• The mechanisms is not well understood
• Metabolic tolerance(An increase in the rate of drug
metabolism)
– Partly responsible in the case of chronic use of barbiturates
• Pharmacodynamics tolerance(changes in
responsiveness of the CNS)
– Greater importance for most sedative-hypnotics
Tolerance…
• In the case of BZDs, down-regulation of brain
BZD receptors
• Minimal tolerance was observed with the use
of zaleplon and eszopiclone.
• The consequences of abuse of these agents
can be defined in both psychological and
physiologic terms
Tolerance…
• Physiologic dependence ;altered physiologic
state that requires continuous drug
administration to prevent withdrawal
syndrome.
Characterized by states of increased anxiety,
insomnia, and CNS excitability that may progress
to convulsions
Tolerance…
• Symptoms of withdrawal are usually more
severe following discontinuance of sedativehypnotics with shorter half-lives.
– Except
for
newer
short-acting
agents(eszopiclone, zolpidem, and zaleplon)
• Most
sedative-hypnotics
causes
physiologic
dependency when used on a long-term basis
Direct toxic action
• Common adverse effects of sedative-hypnotics result
from dose-related depression of the CNS.
• The intensity and incidence of CNS toxicity generally
increase with age
• At low doses; drowsiness, impaired judgment, and
diminished motor skills.
• Sleep driving and other somnambulistic behavior with
no memory of the event.
Direct toxic action…
• Significant dose-related anterograde amnesia(BZDs).
 Impaired ability to learn new information while retrieving previously
learned information.
• This can be utilized for uncomfortable clinical procedures,
eg, endoscopy
 Since the pt is able to cooperate during the procedure but
amnesic regarding it afterward.
• At higher doses, toxicity may present as lethargy or a
state of exhaustion
Direct toxic action…
• Sedative-hypnotics can exacerbate breathing problems
in pts with chronic pulmonary disease and in those
with symptomatic sleep apnea.
• Adverse effects of the sedative-hypnotics that are not
referable to their CNS actions occur infrequently.
• Hypersensitivity reactions, including skin rashes, occur
only occasionally with most drugs of this class.
Direct toxic action…
 FDA pregnancy category;
• BZDs ,either D or X; Barbiturates(most),D.
• Eszopiclone, ramelteon, suvorexant, zaleplon, and
zolpidem , C
• Buspirone ,B
• Barbiturates are absolutely contraindicated, in pts
with a hx of porphyria.
Drug Interactions
• Most common drug interactions;
– Sedative-hypnotics with other CNS depressant drugs.
• Leading to additive effects.
With concomitant use of alcoholic beverages, opioid
analgesics, anticonvulsants, and phenothiazines.
• Enhanced CNS depression ;-antihistamines,
antihypertensive agents, and antidepressant drugs of
the tricyclic class