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Sedative-Hypnotics-I

Dr.U.P.Rathnakar
MD. DIH. PGDHM

www.scribd.com

Sedative-Hypnotics-depress CNS
Sedatives:
Calmness without inducing sleep
Hypnotics:
Produces drowsiness-facilitates onset and maintenance of sleep, Can
be woken up just like from normal sleep, Resembles natural sleep
with EEG characteristics
HYPNOSIS;
Passive state of suggestibility by
artificial means*

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"Sleep is essential for a human being to maintain the
delicate balance of health necessary for its very
existence and survival. Sleep is, therefore, a
fundamental and basic requirement without
which the existence of life itself would be in
peril,"
"Sleep,is a self-rejuvenating element of our life cycle
and is, therefore, part and parcel of human life. The
disruption of sleep is to deprive a person of a basic
priority, resulting in adverse metabolic effects,"
Sedatives
Hypnotics
Hypnotics
HYPNOSIS
Sleep

NREM
NA
Forebrain-slow wave-
thinking
HR,BP, Resp
GH
Muscles relaxed
0-1-2-3-4
REM
5HT
Hind brain-fast wave
dreaming
Fluctuating
Penis erect
Profound relaxation
NREM[60mts]REM[20mts]-Repeats
History
Alcohol & Herbs Since antiquity
Bromide, Chloral hydrate, Paraldehyde
Phenobarbital 1912
2500 barbiturates tested, 50
commercially available
Upto 1960 No others
Then came chlordiazepoxide and other
benzodiazepines*

Benzodiazepines[BZD]
1. Hypnotics:
Diazepam, Nitrazepam, Alprazolam,
Temazepam, Triazolam
2. Anti-anxiety:
Diazepam, Chlordiazepoxide, Oxazepam,
Lorazepam, Alprazolam
3. Anti-convulsants:
Diazepam, lorazepam, Clonazepam, Clobazam
4.Non[Novel]-Benzodizapine hypnotics:
Zopiclone, Zolpidem, Zaleplon*

21
Benzodiazepines[BZD]
1. Short acting
Triazolam, Oxazepam, midazolam
2. Intermediate acting
Lorazepam, Alprazolam, Temazepam,
nitrazepam
3. Long acting:
Diazepam, Clonazepam, flurazepam,
chlordiazepozide
4.Non[Novel]-Benzodizapine hypnotics:
Zopiclone, Zolpidem, Zaleplon*

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Benzodiazepines
Benzene + Diazepine ring
Ph.Action:
CNS: Peripheral
Sedative > Coronary vaso.dil.
Hypnotic > N.M.Block[Toxic doses]
Anxiolytic
Muscle relaxant
Anterograde amnesia*


Action profile of all BZD same-selectivity
different
Sites of action
SleepDep.of ascending reticular
formation
Effect on mental function Limbic
system
Muscle relaxation Medulla.
Ataxia Cerebellum*

Ph.action contd
Sleep;
Onset hastened
Total sleeping time increased
REM cycle increases but duration of REM
Night terrors decrease
Wakes up refreshed
RS: Hypnotic doses no effect. Higher doses depress
vent. & acidocis
CVS: Low doses no effect. High-hypotension,
tachycardia. i.v. increases cor.flow*

Agonist
Antagonist
Novel
Inverse
GABA
A
-Benzodiazepine- Receptor-Cl channel complex

Versatile drug-responsive
machine in the body
Benzodiazepines
Barbiturates,
Zolpidem
Flumazenil
Alcohol
Etomidate,
Propofol
Thiopental.
GABA modulation:
Agonists: BZDP
Inverse agonist: DMCM
BZD antagonist: Flumazenil- Against agonist[BZD] and inverse agonist[DMCM]
Receptor antagonism: Bicuculline [Competitive antagonist @GABA binding site]
GABA A Receptor
GABA
BZD-NO GABA
BZD+ GABA
GABA
BZD
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MOA
By action on GABA rec.
GABA A. [Cl.channel]
GABA is primary ligand.
BZD binds to difft. site & enhances
GABA binding action
BZD frequency of Cl- channel opening
GABA facilitator-Not GABA mimetic*
PK
Absorption[oral]: Except midazolam.
Absorbrd completely
PK variations- Variations in lipid solubility

Metabolism
Phase I[active metabolites] Phase II [conjugation]
Oxazepam, lorazepam, temazepam-directly
conjugation[Safer in elderly] orally well absorbed
Cross placental barrier
I.M; Erratic except lorazepam and midazolam

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Toxicity
Safe drugs
Light headedness, increased reaction time, motor
incordination,-IMPAIRS DRIVING-DANGEROUS
WITH ALCOHOL
Daytime sleepiness
Weakness, headache, blurred vision, vertigo, nausea,
vomiting, diarrhea, Jt.pain, incontinence
Anticonvulsants may increase seizures
Dependence-less than Barbiturates
FLUNITRAZEPAM {ROHYPNOL]-
Date rape drug*
Drug interactions
BZD + Alcohol Excessive CNS dep;.
BZD + Valproate psychotic symptoms
CYP3A4 inhibitors Prolong metabolism of BZD
Acute toxicity
Acute toxicity
Benzodiazepines less dangerous -other
anxiolytic/hypnotic drugs.
This is an important advantage in attempted
suicide.
Prolonged sleep, without depression of respiration
or cardiovascular function.
With alcohol, benzodiazepines can cause severe,
even life-threatening, respiratory depression.
Effective antagonist, flumazenil-Not available for
Barbiturates
Tolerance and dependence
Tolerance (i.e. a gradual escalation of dose
needed to produce the required effect) occurs
with all benzodiazepines-antiepileptic action
Less than barbiturates
Benzodiazepines produce dependence, and this
is a major problem
Withdrawal symptoms
Short-acting benzodiazepines cause more abrupt
withdrawal effects
17
Novel Benzodiazepine receptor agonists
{Non-Benzodiazepine Hypnotics}
Zaleplon. Zolpidem.Zopiclone.
Eszopiclone
Chemical structure does not resemble
Agonists at BZD sites on GABA rec.
Short half life(1-2h)
Amnesia, rarely hallucinations
Preferred hypnotics for short term
use*
16
Novel Benzodiazepine receptor agonists
{Non-Benzodiazepine Hypnotics}
Negligible muscle relaxant
No anticonvulsant
Tolerance and dependence less than
BZDPN
Side effects and overdose same as
BZDPN
Flumazenil effective
Uses of BZD
Anxiolytic .
Status epilepticus.
Muscle relaxant.
Preanaesthetic
Short surgical procedures-amnesia.
Alcohol withdrawal.
With analgesics.
FDC banned*
15
Insomnia-Nature of sleep disruption
Difficulty falling asleep
(sleep onset insomnia)
Frequent or sustained awakenings
(sleep maintenance insomnia)
Persistent sleepiness/fatigue despite
sleep of adequate duration
(non-restorative sleep).
Insomnia
Insomnia-Duration of symptoms
1. Transient:
2. <3 days. Stress. Jet lag. Change of place
3. Short term:
4. 3days-3weeks. Grief, Illness
5. Long term:
6. >3 weeks. Medical problems, psychiatric
disorders.

14
Pharmacotherapy
Alcohol and antihistamines - nonprescription
sleep aids[sleep disruption during the night and
can escalate into abuse, dependence, and
withdrawal ]
Benzodiazepine- most effective and well-
tolerated
zaleplon t12 h;
zolpidem and triazolam with t23 h;
Eszopiclone t of 5.58 h;
Temazepam, lorazepam with t of 612 h

short durations of treatment, intermittent use,
or gradual tapering of the dose
To minimize rebound insomnia and tolerance
Ideal hypnotic
Will not disturb sleep
architecture
No next day effects
No drug interactions
No dependence
REGULAR MOD. EX. IS IDEAL! *
Good sleeping practice
Go to bed only when sleepy
Use bed & bed room only for sleeping & s**
If awake after 20 mts leave the bed room
Getup same time every morning-regardless of
sleep at night
Discontinue coffee & Nicotine (at least
evenings)
Reg.ex.regimen
Avoid alcohol
Relaxation therapy*



13
Flumazanil
BZd receptor antagonist
Against both agonist & inverse agonist
High I pass metabolism
Only i.v.
Used to reverse BZD anesthesia
BZD over dose
0.2mg/mtIf does not respond suspect
other drugs along with BZD like alcohol
*
12
Why BZDs preferred over Barbiturates?[compare and
contrast ]
1. High TI- Very high dose not fatal
2. Hypnotic doses- other systems not
effected
3. Sleep architecture not disturbed
4. Rebound phenomenon less common
5. Does not induce enzymes
6. Lower abuse potential
7. Antidote available*
11

Sedative-Hypnotics-II


Dr.U.P.Rathnakar
MD. DIH. PGDHM

www.scribd.com

10
Barbiturates
Long acting:
Phenobarbitone
Short:
Butobarbitone,
Pentobarbitone,
Ultra short acting:
Thiopentone, Methohexitone*
9
MOA
Site of action: General global CNS
depression
Duration of opening of Cl- channels-
GABA facilitator
Higher concn. GABA mimetic
Inhibit AMPA rec.
Depress Na & K channels
Multiple neuronal targets*
8
Pharmacological actions
CNS: Dose dependent depression
SedationSleep Anesthesia Coma death.
Time taken to sleep
Sleep duration
Hangover common
Impairs learning
Hyperalgesia(No analgesia)
Anticonvulsant
CVS: therapeutic doses hypotension
RS: higher doses depression*

7
PK
Well absorbed
CNS entry- depend on lipid solubility
Termination of action-Metabolism [intermediate lipid
soluble], excretion[Low lipid soluble], redistribution[Highly lipid
soluble]
Thiopentone-Highly lipid solublePenetrates
CNS in 6-10 sec. Anesthesia
Redistribution to other organs Plasma
concn.falls Back diffuses from brain
Conciousness 6-10mts
Ultimate disposal by metabolism*

6
Uses and toxicity
o Uses
Pheno-Epilepsy
Thiopentone- i.v. anesthetic, Narco-analysis
Jaundice-newborn
Not as hypnotic
o Toxicity
o Enzyme inducer
o Abuse, tolerance, dependence, Drug automation
Hangover
Learning disabilities, Confusion, paradoxical
excitement, hyperalgesia
5
Barbiturate poisoning
Suicidal or accidental
Gastric lavage with activated
charcoal
Supportive-Airway, BP, Fluids
Alkaline diuresis
Hemodialysis
No anti dote*
4
C.I.
Intermittent porphyria
Liver and kidney disease
COPD
Sleep apnoea
D.I.
Enzyme inducer reduces effectiveness of
Warfarin, OCP, Tolbutamide, Chloramphenicol
Additive with CNS depressants-
antihistaminics
Complex interaction with Phenytoin-
Competitively inhibits and induces*
3
AIP & barbiturates
Induces
Deficient
Their use by EXPECTANT MOTHERS shortly before
the delivery may result in a floppy infant syndrome,
with the newborns suffering from
hypotonia, hypothermia, lethargy and breathing and
feeding difficulties

The ELDERLY are at an increased risk
of dependence and are more sensitive to the adverse
effects such as memory problems, daytime sedation,
impaired motor coordination and increased risk of
motor vehicle accidents and falls
2
Why BZDs preferred
High TI- Very high dose not fatal
Hypnotic doses- other systems not
effected
Sleep architecture not disturbed
Rebound phenomenon less common
Does not induce enzymes
Lower abuse potential
Antidote available*
Last