Sedative-Hypnotics

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

www.pharmacologyfordummies.blogspot.com
www.scribd.com
 Sedative-Hypnotics
 Sedatives: Deppresses CNS-Calmness &
Drowsiness(Sedation). Slow acting
 Hypnotics: Produces drowsines-
facilitates onset and maintainance of
sleep. Resembles natural sleep with EEG
charecterstics
 HYPNOSIS; Passive state of
sugestibility by artificial means*
Hypnotics Sedatives

Hypnotics

HYPNOSIS
 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*
 Barbiturates

Benzodiazepines

CNS DEP: Sedation Sleep Unconciousness GA  Dep. Of CVS & RS 

Death
•Sleep-Absence wakefulness
•Active process
•1/3 of life spent in sleep
•Biological clock regulates
•Restoration of natural balance
Among neuron
•Sleep-NREM &REM
•NREM 90’-I,II,III,IV REM 5-30
Cycle repeates REM prolongs
Wake up from
•Children-sleep & growth

Physiology of sleep
 NREM REM
 Peacefull  Not
 P.Symp+  Symp act+
 BMR, CO, HR, PVR-Low  High
 Infrequent dreams-no  Vivid, bizarre, sexual
recall
 Muscle relax-except RS
 Muscle flacid
(Ob.apnoea)
 Hypotension  Hypertension
 No eye ball movement  Rapid eye ball
movement*
 GH in stage 3 & 4*
[Children]
 Benzodiazepines[BZD]
1. Hypnotics:
Diazepam, Nitrazepam, Alprazolam, Temazepam,
Triazolam
2. Ant-anxiety:
Diazepam, Chlordiazepoxide, Oxazepam,
Lorazepam, Alprazolam
3. Anti-convulsants:
Diazepam, lorazepam, Clonazepam, Clobazam
4. Non[Novel]-Benzodizapine hypnotics:
Zopiclone, Zolpidem, Zaleplon*
 Benzodiazepines
 Benzene + Diazepine ring
 Ph.Action:
 CNS: Peripheral
• Sedative > Coronary vaso.dil.
• Hypnotic > N.M.Block[Toxic doses]
• Anxiolytic
• Muscle relaxant
• Anterograde amnesia*
 Ph.action contd…
 CNS:
 Not a general depressant
 Action profile of all BZD same-selectivity difft.
 Does not produce “True anesthesia”
 Anti anxiety-not dependent on sedative action
 Anticonvulsant-Tolerance
 Sk.Muscle relaxation-central
 Analgesia-Only Diazepam-i.v.
 No hyperalgesia*
 Ph.action contd…
 Sleep;
 Onset hastened

Total sleeping time increased [stages 3&4 ↓]
 REM cycle increases ↑ but duration of REM ↓
 Night terrors decrease
 Wakes up refreshed
• RS: Hypnotic doses no effect. Higher doses
depress vent. & acidocis [OSA is CI]
• CVS: Low doses no effect. High-hypotension,
tachycardia. i.v. increases cor.flow*
Sites of action

 SleepDep.of ascending reticular

formation
 Effect on mental function Limbic

system
 Muscle relaxation Medulla.

 Ataxia Cerebellum*
 •Versatile drug-responsive
•Agonist machine in the body
•Antagonist •Benzodiazepines
•Novel •Barbiturates,
•Inverse •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]

GABAA-Benzodiazepine- Receptor-Cl channel complex

 BZD

GABA

GABA A Receptor GABA

BZD-NO GABA

BZD+ GABA
 MOA

 GABA Inhibition By action on GABA

rec.
 GABA rec. A & B & C
 A. [Cl.channel]
 GABA is primary ligand.
 BZD binds to difft site & enhances
GABA binding action
 BZD ↑ frequency of Cl- channel opening
 GABA facilitatory-Not GABA mimetic*
 PK
 Absorption:
 PK variations- Variations in lipid solubility
 Absorbrd completely
 Clorazepate-Gastri juice-Nordazepam(Active)
 Prazepam, FlurazepamOnly active ingredients
reach Syst.circulation

 Metabolism
 Metabolized by CYP
 Some yield active metabolites
 Eliminated after conjugation
 Enzyme inhibitors prolong action*
 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
 Duration of action:
 Ultra short acting  Midazolam
 Short acting Triazolam-(Zolpidem)
 Intermediate acting[6-24h) Estazolam,
Temazepam
 Long acting (>24h) Diazepam, Flunazepam,
Quazepam*
 Acute toxicity
 Acute toxicity
 Benzodiazepines less dangerous -other
anxiolytic/hypnotic drugs.
 Agents attempted suicide, this is an important
advantage.
 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
 Side effects during therapeutic use
 Drowsiness, confusion, amnesia and impaired
coordination, -manual skills -driving performance.
Benzodiazepines enhance the depressant effect of
alcohol,.
 The long and unpredictable duration of action of
many benzodiazepines is important in relation to
side effects. Long-acting drugs such as nitrazepam
are no longer used as hypnotics,
 .
 Tolerance and dependence
 Tolerance (i.e. a gradual escalation of dose
needed to produce the required effect) occurs
with all benzodiazepines
 Less than barbiturates [Enz.inducer]
 Benzodiazepines produce dependence, and this
is a major problem
 Withdrawal symptoms
 Short-acting benzodiazepines cause more abrupt
withdrawal effects
 Novel Benzodiazepine receptor agonists
{Non-Benzodiazepine Hypnotics}

 Chemical structure does not resemble

 Agonists at BZD sites on GABA rec.
 Short half life(1-2h)
 Zaleplon. Zolpidem.Zopiclone.
Eszopiclone
 Amnesia, rarely hallucinations
 Short term use*
Uses of BZD
 Anxiolytic .
 Status epilepticus.
 Muscle relaxant.
 Short procedures.
 Alcohol withdrawal.
 With analgesics.
 FDC banned*
 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: <3 days. Stress. Sleep hygiene. Jet
lag. Envn.
2. Short term:3d-3weeks. Grief, Illness
3. Long term: >3 weeks. Medical problems,
psychiatric disorders.
Insomnia
 Persistent insomnia can lead to impaired daytime
function, injury due to accidents, and the development of
major depression.
 Chronic insomnia - increased utilization of health care
resources
 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 →→t½1–2 h;
 zolpidem and triazolam with t½2–3 h;
 Eszopiclone t½ of 5.5–8 h;
 Temazepam, lorazepam with t½ of 6–12 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! *

 Treatment of insomnia
 Psychological:
 Go to bed only when sleepy
 Use bed & bed room only for sleeping & sex
 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*
Treatment of insomnia
 Lorazepam-0.5mg.HS
 Temazepam-7.5-15mg HS

 Zolpidem, Zaleplon- 5-10mg. HS

 Younger-Double dose

 1-2 weeks.

 Intermittent therapy

 No Barbiturates*
 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/mtIf does not respond suspect

other drugs along with BZD like alcohol *

 Why BZDs preferred over Barbiturates?

 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*
Barbiturates
 Long acting:
Phenobarbitone
 Short: Butobarbitone,
Pentobarbitone,
 Ultra short acting:
Thiopentone,
Methohexitone*
 MOA
 Site of action: General global CNS
depression
 ↑Duration of opening of Cl- channels-
GABA facilitatory
 Higher concn. GABA mimetic

 Inhibit AMPA rec.

 Depress Na & K channels

 Multiple neuronal targets*

 Pharmacological actions
 CNS: Dose dependent depression
 SedationSleep Anesthesia Coma  death.
 ↓Time taken to sleep
 ↑Sleep duration
 Hangover common
 Impairs learning
 Hyperalgesia(No analgesia)
 Anticonvulsant
 CVS: Hypotension
 RS: Depression*
 PK
 Well absorbed
 CNS entry depend on lipid solubility
 Termination of action-Metabolism, excretion,
redistribution
 Thiopentone-Highly lipid solublePenetrates
CNS in 6-10 sec. Anesthesia
Redistribution to other organs Plasma
concn.falls Back diffuses from brain
Conciousness 6-10mts Ultimate disposal
by metabolism*
 Uses and toxicity
o Uses
 Pheno-Epilepsy
 Thiopentone- i.v. anesthetic, Narcoanalysis
 Cong.non-hemolytic jaundice
 Not as hypnotic
o Toxicity
 Hangover
 PK & PD tolerance, dependence
 Confusion, paradoxical excitement
 Abuse liability, withdrawal symptoms,
hypersensitivity*
 Barbiturate poisoning
 Suicidal or accidental
 Gastric lavage with activated

charcoal
 Supportive-Airway, BP, Fluids

 Alkaline diuresis

 Hemodialysis

 No anti dote*
 CI And DI
 C.I.

 Intermittent porphyria

 Liver and kidney disease

 COPD

 Sleep apnoea

• D.I.
 Enzyme inducer reduces effectiveness of
Warfarin, OCP, Tolbutamide, Chloramphenicol
 Complex interaction with Phenytoin-
Competitively inhibits and induces*
 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

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
 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*