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SEDATIVE HYPNOTIC DRUGS

Aditia Retno Fitri

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OUTLINES
Sleep
Hypnotic vs Sedative
Hypnotic Sedative Drugs
Benzodiazepine
Barbiturates
Miscellaneous Agents
Summary

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SLEEP
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Normal sleep
Normal sleep cyclic and repetitive, consists of distinct
stages,based on three physiologic measures: the
electroencephalogram, the electromyogram, and the
electronystagmogram.

Non-rapid eye movement(NREM) sleep: 70%-


75%
Stage 1,2
Stage 3,4:slow wave sleep, SWS
Rapid eye movement(REM) sleep

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SEDATIVE - HYPNOTIC
SEDATIVE
Drugs that have an inhibitory effect on the
CNS to the degree that they reduce:
Nervousness
Excitability
Irritability without causing sleep
(McKenry et al., 2003)

An effective sedative (anxiolytic) agent should reduce


anxiety and exert a calming effect with little or no
effect on motor or mental functions.
(Katzung et al., ed 11)

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HYPNOTICS

Calm or soothe the CNS to the point that they


cause sleep
A hypnotic drug should produce drowsiness and
encourage the onset and maintenance of a state of
sleep that as far as possible resembles the natural
sleep state.
A sedative can become a hypnotic if it is given in
large enough doses  dose dependent

(Katzung; Goodman & Gilman)

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CNS Depression

Sedation
Hypnosis
General Anesthesia
Poisoning
Death

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Anxiolytics: reduce anxiety

Sedatives: decrease activity, calming effect

Hypnotics: induce sleep

Some drugs have anxiolytic and


sedative/hypnotic effects.

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SEDATIVE-HYPNOTIC DRUGS

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SEDATIVE-HYPNOTIC
SEDATIVE-HYPNOTIC DRUGS
DRUGS

SEDATIVE-HYPNOTICS

Benzodiazepines Barbiturates Miscellaneous agents

Short Ultra
action action
Intermediate Short Buspirone
action action Chloral hydrate
Long Long Zaleplon
action action Zolpidem
Ramelteon

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GABA System
is the major inhibitory neurotransmitter in the brain.
It has specific receptors in chloride channels present on
the membrane of post synaptic neurons.
 regulates the entrance of chloride into the postsynaptic cells.

Binding of GABA to its receptor (GABA A receptor)


results in opening of the chloride channel and increased
conductance of cl¯ ions to inside the post-synaptic
neuron.  hyperpolarization of the postsynaptic neuron
and decreased synaptic neurotransmission.

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Site and Structure of Action

Site of action is the GABAA receptor


Structure of GABAA receptor
Comprised of 5 subunits
2 α subunits (to which GABA binds)
2 β subunits (to which barbiturates bind)
1 γ subunit (to which benzodiazepines bind)

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Characteristics of an “Ideal” Hypnotic

Ideal Hypnotic

Pharmacokinetic Pharmacokinetic Side


Properties Effect Effect
Rapid absorption • Rapid sleep induction • No residual sedation
No active metabolites • Physiological sleep • No respiratory
Optimal half-life pattern depression
• Mechanism other than • No ethanol interaction
general CNS depression • No tolerance
• Sleep maintenance • No physical
• Improved Daytime dependence
Function • No rebound insomnia
• No effect on memory
Adapted from Bartholini G. In: Sauvanet JP, Langer SZ, Morselli PL,
eds. Imidazopyridines in Sleep Disorders. 1988:1-9.
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Sedative/hypnotics
death Most
non-benzodiazepine
sedative/hypnotics
surgical
anesthesia

coma
Benzodiazepines,
Zolpidem, Zaleplon
unconsciousness

sleep

sedation

Drug dose 20
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BENZODIAZEPINES

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BENZODIAZEPINES : Pharmacodynamic
• act selectively on gamma-aminobutyric acid A
(GABAA) receptors, which mediate fast inhibitory
synaptic transmission through the CNS.
• bind to the gamma sub-unit of the GABA-A receptor.
• causes an allosteric (structural) modification of the
receptor that results in an increase in GABA A
receptor activity.
• not substitute for GABA, which bind at the alpha sub-unit,
but increase the frequency of channel opening events
which leads to an increase in chloride ion conductance
and inhibition of the action potential

• The antagonist – f l u m a z e n i l

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BENZODIAZEPINES : Pharmacodynamic

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BENZODIAZEPINES: Pharmacokinetics

 Absorption:
 well absorbed if given orally , Cmax reached in
about 1 h
 Binding:
 strongly bound to plasma proteins
 Distribution:
 large Vd: accumulation in body fat (high lipid
solubility)
 Metabolism:
 Hydroxylation
 conjugation with glucuronic acid
 short-, medium- and long-acting BZ
 the role of N-desmethyldiazepam

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BENZODIAZEPINES : Biotransformation

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BENZODIAZEPINES: Short Acting and the Elderly

Short-lasting benzo’s are not converted to active


intermediates; they are metabolized directly into
inactive products
The elderly have a reduced ability to metabolize
long-acting benzo’s (and their active metabolites)
Pharmacokinetics are not drastically altered with
the short-acting benzo’s

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Benzodiazepine Binding Site Ligands
Three types of ligand-benzodiazepine receptor interactions have been
reported:
(1)Agonists
•facilitate GABA actions  occurs at multiple BZ binding sites
•nonbenzodiazepines zolpidem, zaleplon, and eszopiclone are selective
agonists at the BZ sites that contain an 1 subunit.
(2) Antagonists
•are typified by the synthetic benzodiazepine derivative flumazenil, which
blocks the actions of benzodiazepines, eszopiclone, zaleplon, and
zolpidem
(3) Inverse agonists
(1)act as negative allosteric modulators of GABA-receptor function.
(2)Their interaction with BZ sites on the GABAA receptor can produce
anxiety and seizures, an action that has been demonstrated for several
compounds, especially the -carbolines, eg, n-butyl--carboline-3-
carboxylate (-CCB). In addition to their direct actions, these molecules
can block the effects of benzodiazepines. 31
Pharmacological effects
Those compounds that bind and enhance the
inhibitory actions of GABA are complete agonists
(Ex) Lorazepam, midazolam, etc.
Those compounds that bind with “less than
complete agonist action” are termed partial agonists
(Ex) Ambien (zolpidem)
Those compounds that bind and decrease the
inhibitory actions of GABA are inverse agonists

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Receptor Ligands

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Benzodiazepines: Main Effects
The main effects of benzodiazepines are:
reduction of anxiety and aggression
sedation and induction of sleep
reduction of muscle tone and coordination
anticonvulsant effect
anterograde amnesia.

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Benzodiazepines: Unwanted Effects

Unwanted effects
• acute overdosage
• effects occuring during normal therapeutic use
• tolerance and dependence

• acute overdosage (BZs are relatively safe in overdose)


• BZs produce prolonged sleep, without serious
depression of respiration or cardiovascular function
• Severe even life-threatening respiratory
depression may appear in BZ combination with
other CNS depressants, particularly alcohol.
• Acute overdosage can be counteracted with
flumazenil
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Benzodiazepines: Unwanted Effects
• unwanted effects occuring during therapeutic
use
• Influence of manual skills (such as driving performance) due to
drowsiness, confusion, amnesia and impaired coordination
• enhance of depressant action of other drugs (in a more than
additive way)
• tolerance , dependence
• Tolerance (gradual escalation of dose needed to produce the
required effect) occurs with all BZs. T.appears to represent a
change at the receptor level.
• Dependence –In human subjects and patients, stopping BZ
treatment after weeks and months causes an increase in
symptoms of anxiety, together with tremor and dizziness.
• The withdrawal syndrome: short acting BZs cause more abrupt
withdrawal effects
• Addiction (-craving -severe psychological dependence) is not a
major problem. 36
Benzodiazepine Therapy

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Effects on Pregnancy
Benzodiazepines (and their metabolites) can freely
cross the placental barrier and accumulate in fetal
circulation
Administration during the first trimester can result in fetal
abnormalities
Administration in third trimester (close to the time of birth)
can result in fetal dependence, or “floppy-infant
syndrome”
Benzodiazepines are also excreted in the breast
milk
 

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BARBITURATES

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Barbiturates: Pharmacodynamic

BA: the sleep-inducing properties were discovered early


in the 20th century . Until the 1960s, they formed the largest
group of hypnotics and sedatives in clinical use.

Pharmacodynamics:
•increase the duration of the GABA-gated chloride channel
openings.
•At high concentrations, the barbiturates may also be GABA-
mimetic, directly activating chloride channels.
•β subunits binding site in GABA receptor
•more pronounced central depressant effects

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Barbiturates : Pharmacokinetics

Absorption
small intestine

Distribution
lipid solubility
rapidly cross placenta

Elimination
liver microsomal enzymes
renal tubular reabsorption

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Barbiturates : Clinical Effect

CNS depression

Respiratory depression

CV depression
decreased myocardial contractility, vasodilation,
hypotension

GI motility inhibition

Poor safety , easy to cause dependence


• The application has been declining and is mainly used for anticonvulsant ,
antiepilepsia and anaesthesia .
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Table 12-3 Barbiturates: Onset and Duration
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Barbiturates: Disadvantage of use

• if given in a large dose


• death from respiratory and cardiovascular depression
(flumazenil not effective)
• a high degree of tolerance:
• BA strongly induce the synthesis and activity of hepatic CYP450
and conjugating enzymes thus increasing the rate of metabolic
degradation of many other drugs
• drug-drug interactions
• dependence
BA are now little used
as anxiolytic and hypnotic drugs

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Barbiturate Poisoning
CNS system
consciousness change
respiratory depression
areflexia

CV system
low cardiac output

• GI system
– ileus

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MISCELLANEOUS AGENTS

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Ramelteon : Melatonin receptors
Pharmacodynamic:
Melatonin receptors  circadian rhythms
an agonist at MT1 and MT2 melatonin receptors
located in the suprachiasmatic nuclei of the brain.
no direct effects on GABAergic
neurotransmission

Indication
reduced the latency of persistent sleep with no
effects on sleep architecture and no rebound
insomnia or significant withdrawal symptoms.
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Ramelteon: Melatonin Receptors ....cont’d
Pharmacokinetic
rapidly absorbed per oral administration
first-pass metabolism!!!!
forming an active metabolite with longer half-life (2–5 hours)
The CYP1A2 isoform and CYP2C9of cytochrome P450 are involved.

Drug Interaction
should not be used in combination with :
inhibitors of CYP1A2 (eg, ciprofloxacin, fluvoxamine, tacrine, zileuton) or CYP2C9
(eg, fluconazole)
The CYP inducer rifampin markedly reduces the plasma levels of both ramelteon
and its active metabolite.
caution in patients with liver dysfunction.

Adverse effects
dizziness, somnolence, fatigue, and endocrine changes as well as
decreases in testosterone and increases in prolactin.
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Buspirone: 5 -HT1A -receptor agonists
Pharmacodynamic:
selective anxiolytic effects  relieves anxiety without causing marked
sedative, hypnotic, no anticonvulsant or muscle relaxant properties. \
does not interact directly with GABAergic systems.
a partial agonist at brain 5-HT1A receptors, but it also has affinity for
brain dopamine D2 receptors.
no rebound anxiety or withdrawal signs on abrupt discontinuance.
not effective in blocking the acute withdrawal syndrome from abrupt
cessation of use of benzodiazepines
minimal abuse liability.
anxiolytic effects of buspirone may take >1week to become
established less effective in panic disorders

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Buspirone: 5 -HT1A -receptor agonists
Pharmacokinetic:
rapidly absorbed orally  extensive first-pass metabolism
The elimination half-life of buspirone is 2–4 hours, and liver
dysfunction may slow its clearance.
Rifampin, an inducer of cytochrome P450, decreases the half-life of
buspirone; inhibitors of CYP3A4 (eg, erythromycin, ketoconazole,
grapefruit juice, nefazodone) can markedly increase its plasma levels.

Adverse effect:
causes less psychomotor impairment than benzodiazepines
does not potentiate effects of conventional sedative-hypnotic drugs,
and elderly patients do not appear to be more sensitive to its actions.
Nonspecific chest pain, tachycardia, palpitations, dizziness,
nervousness, tinnitus, gastrointestinal distress, and paresthesias and
a dose-dependent pupillary constriction
FDA category B drug in terms of its use in pregnancy.
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Differences between buspirone and benzodiazepines:
1- The full anxiolytic effect of buspirone takes several
weeks to develop, whereas the anxiolytic effect of the
benzodiazepines is maximal after a few days of therapy.
2- In therapeutic doses, buspirone has little or no sedative
effect and lacks the muscle relaxant and anticonvulsant
properties of the benzodiazepines.
3- Buspirone does not potentiate the central nervous
system depression caused by sedative–hypnotic drug or
by alcohol
4- Buspirone does not prevent the symptoms associated
with benzodiazepine withdrawal.

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Zolpidem

Effect:
• binds selectively to the BZ1 subtype of BZ receptors
and facilitates GABA-mediated neuronal inhibition
Useful for the short-term treatment of insomnia
Primarily a sedative (rather than an anxiolytic)
are antagonised by f l u m a z e n i l
risk of tolerance and dependence < BZ

Pharmacokinetics:
Rapidly absorbed in the GI tract following oral
administration (75% reaches plasma)
Metabolized in the liver and excreted by the kidney’s
Dosage reduction in hepatic dysfuction, elderly

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Zaleplon & Zopiclone
Short half-life resembles zolpidem, t1/2 = 1h
Rapid onset and short duration of action are favorable
properties for those patients who have difficulty falling
asleep.
Only approx. 30% of an orally administered dose reaches the
plasma, and most of that undergoes first-pass elimination
Half as potent as zolpidem
Improves sleep quality w/o rebound insomnia, and little
chance of developing dependency

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Sedative-Hypnotic: Misuse and Abuse
Motivational Factors
The search for sleep
Coping with stress
Appetitive drug use-motivated by desire for pleasurable
responses and sensations
Escape-avoidance drug use-motivated by desire for relief
from an unpleasant sensation, tension, fear, or anxiety
Potentiating (synergistic)- exaggerated depressant effect
Offset effects of stimulant drugs

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Sedative-Hypnotic: Withdrawal Syndrome
First 12-15 hours, patient appears to improve

16+ hours
Restless, anxious, tremulous, weak, abdominal cramping
Vomiting, orthostatic hypotension, tremors, increased deep tendon
flexion, convulsions

Days 2-3
Delirium, hallucinations (persecutory) disorientation to time & place
Once delirium starts can’t be reduced by administration of other
sedative hypnotics-has to run its course
Includes hyperthermia (increased body temp), exhaustion,
cardiovascular collapse & sometimes death

Depending upon type of drug, withdrawal symptoms reach peak severity


at days 2-3 & last upwards of a week ( & in some cases, some of the
symptoms may last several weeks)

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Sedative-Hypnotics: Clinical Uses
For relief of anxiety
For insomnia
For sedation and amnesia before and during medical
and surgical procedures
For treatment of epilepsy and seizure states
As a component of balanced anesthesia (intravenous
administration)
For control of ethanol or other sedative-hypnotic
withdrawal states
For muscle relaxation in specific neuromuscular
disorders
As diagnostic aids or for treatment in psychiatry

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HALF-LIFE EFFECTS ON PLASMA LEVELS

400
350 ACCUMULATES
RELATIVE CONCENTRATION

NIGHT & DAY


300
250
200
150
HIGH AFTER
100 WAKE

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0 HIGH EARLY
0 20 40 60 80 100 120 140 LOW BEFORE
HOURS after first dose ( taken each bedtime ) WAKE
HALF LIVES OF HYPNOTICS SLEEP TIME
~ 8 HOURS ~ 2 HOURS ~ 48 HOURS +

EXAMPLES: TEMAZEPAM TRIAZOLAM DIAZEPAM


LORAZEPAM ZOLPIDEM FLURAZEPAM
OXAZEPAM ZALEPLON QUAZEPAM
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DRUG METABOLISM:
TOO SHORT: EARLY
AWAKENING. TOO
LONG: HANGOVER.
SOMETIME BOTH!

TIME IN BED HOURS AFTER BEDTIME


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SUMMARY

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Summary

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Summary

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Summary

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THANK YOU
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