SEDATIVE HYPNOTICS

Introduction
• An effective sedative (anxiolytic) agent should
reduce anxiety and decreases activity, moderates
excitement, and calms the recipient
• A hypnotic drug should produce drowsiness and
encourage the onset and maintenance of a state of
sleep.
• Hypnotic effects involve more pronounced
depression of the CNS than sedation, and this can
be achieved with many drugs in this class simply by
increasing the dose
• Ramelteon and tasimelteon, melatonin receptor agonists, are newer
hypnotic drugs
• Buspirone is a slow-onset anxiolytic agent whose actions are quite
different from those of conventional sedative-hypnotics
• antihistaminic agents including hydroxyzine and promethazine are
also sedating.
• antihistaminic drugs with hypnotic effects, eg, diphenhydramine and
doxylamine, are available in over-the-counter sleep aids.
barbiturates

benzodiazepines
 Mechanism of action
• benzodiazepines potentiate GABAergic
inhibition at all levels of the neuraxis, including
the spinal cord, hypothalamus, hippocampus,
substantia nigra, cerebellar cortex, and cerebral
cortex.
• The benzodiazepines do not substitute for GABA
but appear to enhance GABA’s effects
allosterically at alpha1 & Gamma 2 subunit
interface ,without directly activating GABAA
receptors or opening the associated chloride
channels.
• increase in the frequency of channel-opening
• Barbiturates also facilitate the actions of GABA at multiple sites in
the CNS, but—in contrast to benzodiazepines—they appear to
increase the duration of the GABA-gated chloride channel
openings.
• At high concentrations, the barbiturates may also be GABAmimetic,
directly activating chloride channels by binding at sites distinct from
the benzodiazepine binding sites.
• Barbiturates also prolong inhibitory effect of glycine
• Barbiturates are less selective in their actions than benzodiazepines,
because they also depress the actions of the excitatory
neurotransmitter glutamic acid via binding to the AMPA receptor.
• This multiplicity of sites of action of barbiturates may be the basis
for their ability to induce full surgical anesthesia ( and for their
more pronounced central depressant effects (which result in their
low margin of safety) compared with benzodiazepines and the
newer hypnotics.
Benzodiazepines
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.
 Pharmacological Actions
1. Reduction of anxiety
At low doses, the benzodiazepines are anxiolytic. They are
thought to reduce anxiety by selectively enhancing GABAergic
transmission in neurons having the α2 subunit in their GABAA
receptors, thereby inhibiting neuronal circuits in the limbic
system of the brain.
2. Sedative/hypnotic
All benzodiazepines have sedative and calming properties, and
some can produce hypnosis (artificially produced sleep) at
higher doses.
The hypnotic effects are mediated by the α1 -GABAA receptors.
3. Anterograde amnesia
Temporary impairment of memory with the use of the
benzodiazepines is also mediated by the α1 -GABAA
receptors. The ability to learn and form new memories is
also impaired.
4. Anticonvulsant
• This effect is partially, although not completely, mediated
by α1 -GABAA receptors.
• At high dose, with marked sedation by most of
barbiturates and some BZD.
• Phenobarbital and clonazepam cause selective
anticonvulsant action with less severe sedation
• High doses of diazepam,lorazepam & phenobarbital in
status epilepticus
5. Muscle relaxant
• At high doses, the benzodiazepines relax the spasticity of skeletal muscle,
probably by increasing presynaptic inhibition in the spinal cord, where the
α2 -GABAA receptors are largely located.
• Baclofen is a muscle relaxant that is believed to affect GABA receptors at the
level of the spinal cord. hyperpolarization via k channel
• Diazepam for specific spasticity states including cerebral palsy
6. Anesthesia
• At high dose cause LOC, amnesia, suppression of reflexes
• By most barbs. ( thiopental) and certain BZD midazolam
7. Medullary depression
High doses especially of alcohols and barbs. Cause depression of medullary
neurons leading to respiratory arrest, hypotension and cardiovascular collapse.
8. Tolerance and dependence
• Tolerance – decrease in responsiveness- occurs when used chronically
• Cross tolerance among different subgroups
• Psychological dependence—compulsive use of drugs-abstinence
syndrome(withdrawal state)
• Includes anxiety, tremors, hyperreflexia, seizures
• Dependence liability of Z drugs is less than benzodiazepines bcz of minimal
withdrawal effects
 Therapeutic uses
1. Anxiety disorders
• panic disorder, generalized anxiety disorder (GAD), social
anxiety disorder, performance anxiety, and extreme
phobias, such as fear of flying.
• treating anxiety related to depression and schizophrenia.
• should be reserved for severe anxiety
• Because of their addictive potential, they should only be
used for short periods of time.
• For panic disorders, alprazolam is effective for short- and
long-term treatment, although it may cause withdrawal
reactions
• The longer-acting agents, such as clonazepam , lorazepam ,
and diazepam , are often preferred in patients with anxiety
2. Sleep disorders
• decrease the latency to sleep onset and increase stage II of non–
rapid eye movement (REM) sleep.
• Both REM sleep and slow-wave sleep are decreased.
• In the treatment of insomnia, it is important to balance the sedative
effect needed at bedtime with the residual sedation (“hangover”)
upon awakening.
• triazolam is effective in treating individuals who have problems
falling asleep. The risk of withdrawal and rebound insomnia is higher
with triazolam than with other agents.
• Intermediate-acting temazepam is useful for patients who
experience frequent awakenings and have difficulty staying asleep.
Temazepam should be administered 1 to 2 hours before the desired
bedtime.
• Long-acting flurazepam is rarely used, due to its extended half-life,
which may result in excessive daytime sedation and accumulation of
the drug, especially in the elderly.
• Zolpidem, zaleplon , eszopiclone have rapid onset, minimal effect on
3. Amnesia
• The shorter-acting agents are often employed
as premedication for anxiety-provoking and
unpleasant procedures, such as endoscopy,
dental procedures, and angioplasty.
• They cause a form of conscious sedation,
allowing the patient to be receptive to
instructions during these procedures.
• Midazolam is used to facilitate anterograde
amnesia while providing sedation prior to
anesthesia.
4. Seizures
• Clonazepam is occasionally used as an
adjunctive therapy for certain types of
seizures
• lorazepam and diazepam are the drugs of
choice in terminating status epilepticus.
• Due to cross-tolerance, chlordiazepoxide,
clorazepate, diazepam, lorazepam, and
oxazepam are useful in the acute treatment of
alcohol withdrawal and reduce the risk of
withdrawal-related seizures.
• Muscular disorders
• Diazepam is useful in the treatment of
skeletal muscle spasms and in treating
spasticity from degenerative disorders, such as
multiple sclerosis and cerebral palsy.
• Bipolar disorder ( clonazepam)
 Dependence
• Psychological and physical dependence can
develop if high doses of benzodiazepines are given
for a prolonged period.
• All benzodiazepines are controlled substances.
• Abrupt discontinuation of these agents results in
withdrawal symptoms, including confusion,
anxiety, agitation, restlessness, insomnia, tension,
and (rarely) seizures.
• 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
 Adverse effects
• Drowsiness and confusion .
• Ataxia (loss of coordination)occurs at high doses and
precludes activities that require fine motor
coordination, such as driving an automobile.
• Cognitive impairment (decreased recall and retention of
new knowledge) can occur with use of benzodiazepines.
• Benzodiazepines should be used cautiously in patients
with liver disease.
• Alcohol and other CNS depressants enhance the
sedative–hypnotic effects of the benzodiazepines.
 Benzodiazepine Antagonist
• Flumazenil is a GABA receptor antagonist that rapidly reverses
the effects of benzodiazepines.
• The drug is available for intravenous (IV) administration only.
• Onset is rapid, but the duration is short, with a halflife of about
1 hour.
• Frequent administration may be necessary to maintain reversal
of a long-acting benzodiazepine.
• Administration of flumazenil may precipitate withdrawal in
dependent patients or cause seizures if a benzodiazepine is
used to control seizure activity.
• Dizziness, nausea, vomiting, and agitation are the most
common adverse effects.
 ATYPICAL SEDATIVE HYPNOTICS
1. Buspirone
• Selective anxiolytic
• Minimal CNS depressant
• Does not effect driving skill
• No anticonvulsant or muscle relaxant properties
• Interacts with 5HT1a receptors as a partial agonist
• Slow onset
• Less effective in panic disorders
• Tolerance dependence is minimal with chronic use
• Little rebound anxiety or withdrawal symptoms
• Side effect includes tachycardia, paresthesias, pupillary constriction,
GI distress
• Minimal abuse liability
• Not a schedule controlled drug
 Melatonin receptor agonists
2. Ramelteon & tasimelteon
• Activate melatonin receptors in SCN
• Decrease latency of sleep onset with minimal
rebound insomnia or withdrawal symptoms
• No direct effect on GABA ergic neurons
• Minimal abuse liability
• Not a controlled substance
• Side effects include dizziness, fatigue,
decrease testosteron and increased prolactin
 Orexin antagonist
• Suvorexant
• Peptide found in hypothalamus
• Involve in wakefullnes
• Antagonist of OX1R & OX2R