Professional Documents
Culture Documents
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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.
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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)
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HYPNOTICS
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CNS Depression
Sedation
Hypnosis
General Anesthesia
Poisoning
Death
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Anxiolytics: reduce anxiety
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SEDATIVE-HYPNOTIC DRUGS
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SEDATIVE-HYPNOTIC
SEDATIVE-HYPNOTIC DRUGS
DRUGS
SEDATIVE-HYPNOTICS
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.
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Site and Structure of Action
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Characteristics of an “Ideal” Hypnotic
Ideal Hypnotic
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
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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
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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
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
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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
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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
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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 +
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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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