Sedative-Hypnotics and Anxiolytic Agents
1. Hypnotics
a. Drugs that can induce sleep
b. Use in the treatment of Insomnia
2. Sedative
a. Drug that can reduce the responsiveness to any level of
excitement
3. All of the sedative-hypnotic drugs are dose dependent
a. Sedation  Hypnosis  Anaesthesia  Coma  Death
Sleep Pattern

Generally, sleep is divided into 2 patterns, which are
o Non - Rapid Eye Movement (REM) sleep
 Slow wave sleep (on the EEG)
 Also called as the deep sleep
 Consist of 75% of total sleep
 Can be further divided into different stages
 N1 stage
o Transition between awake to drowsy sleep
o Simple way, put it like this – you are
 In shallow sleep
 Can jerk awake easily
 Slightly concious of your surrounding
 Not dreaming
 No rapid eye movement
 N2 stage
o Periods where the brain is inhibiting processing to keep the
sleeper in a tranquil state
o Loss conciousness towards the surrounding
o Decrease muscle tone
 N3 stage
o This is the stage in which the occurrence of parasomnias
such as
 Night terrors
 Nocturnal enuresis
 Sleepwalking
 Somniloquy
 N4 stage
o Cerebral sleep
o Rapid Eye Movement (REM) sleep
 Rapid wave sleep (on the EEG)
 Characterized by
 Rapid eyes movement
 Increase respiratory rate
 Increase brain activity
 Most memorable dreams occurred at this period of sleep
 Sleep proceeds in cycles of REM and NREM, the order normally being
N1 → N2 → N3 → N2 → REM

There is a greater amount of deep sleep (stage N3) earlier in the sleep
cycle, while the proportion of REM sleep increases later in the sleep
cycle and just before natural awakening
Sedative-Hypnotic Drugs
1. Barbiturate
a. Phenobarbital
b. Thiopental
2. Benzodiazepine
a. Clonazepam
b. Diazepam
c. Midazolam
3. Newer Hypnotic
a. Zolpidem
b. Zaleplon
c. Eszopiclone
4. Miscelaneous
a. Antihistamine
b. Chloral hydrate
c. Ethanol
Sedative-Hypnotic Drugs
Drugs
Barbiturates


Phenobarbital
Pentobarbital
Benzodiazepines




Clonazepam
Diazepam
Lorazepam
Midazolam
Benzodiazepine Antagonist
 Flumazenil
MOA
 Inhibit the GABAa receptors
Features
 Given only through IV
Clinical Uses
 Reverse the Benzodiazepine
anaesthesia
 Treatment of
Benzodiazepine overdosage
Pharmacokinetic
Absorption
 Very well absorbed orally
Distribution
 Can pass BBB and easily
deposited in body
compartments
 Has a narrow Therapeutic
Index, therefore close
monitoring is needed
Metabolism
 Hepatic metabolism
 It is a CYP450 inducer;
therefore may increase
metabolism of other drugs
Excretion
 Renal clearence
Absorption
 Well absorbed orally
Distribution
 Pass the BBB and
deposited in many of
body compartments
 Has wider Therapeutic
window; therefore has
better safety margin
Metabolism
 Hepatic metabolism
 Diazepam undergoes
Enterohepatic recycling
Excretion
 Renal
 Bile
Mechanism of Action











Act on most combinations of
GABA-A receptor subunits
Increase the mean open
time of GABA-A activated
chloride channels
Slow the rate of dissociation
of GABA from GABA-A
receptors
At high concentrations,
directly activate GABA-A
receptors
Increase the maximum
effect of GABA on GABA-A
receptors
Binds to Alpha1 and Alpha2
Benzodiazepine sites on the
GABA receptors
This will directly increase the
effect of GABA by increasing
the duration of GABA-gated
Chloride channels opening
 IPSP
Benzodiazepines do not
enhance the maximal
response to GABA
Benzodiazepines act only on
GABA-A receptors that
contain γ2-subunits – such
receptors may constitute
only 20% of the GABA-A
receptors in brain
Benzodiazepines enhance
the effects of GABA by
increasing the frequency of
opening and closing of the
channels.
Pharmacological
Effects





Sedation in a low dose
Hypnosis
o Shortens time to
sleep
o Increase the sleep
time
o Reduces night
awakening
o Reduces the REM
and Non-REM
despite the
increased sleep
time
o Disrupt sleep cycle
Muscle relaxant
Anxiolytic
Anticonvulsant
Adverse Effects














CNS depression –
respiratory depression
Hangover syndrome
Impaired
concentration and
reaction
Impaired memory
Nightmares due to
reduced REM
Tolerance
Dependance
Withdrawal syndrome
upon discontinuation
Rebound effects
Relapse effects
Less commonly cause
Hangover syndrome
Impairment of
o Cognitive
function
o Concentration
and reaction
o Memory
Less marked
Withdrawal syndrome
after discontinuation
Long term use and
high dose may lead
to
o Dependance
o Tolerance
Drugs
Newer
Hypnotics



Zolpidem
Zaleplon
Eszopiclone
Pharmacokinetic
Absorption
 Readily absorb
orally
Distribution
 Readily pass the BBB
and accumulate in
body
compartments
Metabolism
 Undergoes hepatic
metabolism
 Some produces
active metabolites
Excretion
 Renal
 Bile
Mechanism of Action
Selectively binds to
the Alpha1 site on
the GABA receptors
 Due to this
selectivity, it is only
be given for the
treatment of
Insomnia

Pharmacological Effects
 Due to its selectivity, it
does not have
o Hangover
syndrome
o Muscle relaxation
o Anticonvulsant
o Significant REM
sleep depression










Adverse Effects
Nausea
Vomiting
Anterograde amnesia
Hallucinations, through all
physical senses, of varying
intensity
Delusions
Altered thought patterns
Ataxia or poor motor
coordination
Euphoria and/or dysphoria
Increased appetite
Increased Libido or decreased
libido/destrudo
Anxiolytics
Drugs
Buspirone
Pharmacokinetic
Absorption
 Readily absorp
orally
 Very low
bioavailibility – 5%
Distribution
 Highly plasma
protein bound
Metabolism
 Undergoes CYP450
metabolism
 Short half life
Excretion
 Renal
 Bile
Mechanism of Action
Pharmacological Effects
 Partial agonist of the  Slow onset anxiolytic
5-HTA1 Serotonin
effects
receptors
o Takes up to 2
 Has also affinity
weeks
towards
o D2
Indication
Dopaminergic
 Use in the treatment
receptors
of Generalized
ChronicAnxiety State






Adverse Effects
Dizziness
Nausea
Headache
Nervousness
Lightheadedness
Excitement