DR.

SUKANTA SEN
Professor
Deptt. Of Pharmacology
Normal sleep cycle consists of- NREM & REM phase.

A sedative drug decreases activity, moderates excitement, and calms

the recipient,
whereas a hypnotic drug produces drowsiness and facilitates the onset
and maintenance of a state of sleep that resembles natural sleep in its
electroencephalographic characteristics and from which the recipient can
be aroused easily.

Categories of Insomnia. The National Institute of Mental Health

Consensus Development Conference (1984) divided insomnia into three
categories:
Insomnia is one of the most common complaints in general
medical practice, and its treatment is predicated on proper
diagnosis.
Categories of Insomnia:

Transient insomnia lasts less than 3 days and usually is

caused by a brief environmental or situational stressor.
 It may respond to attention to sleep hygiene rules.
If hypnotics are prescribed, they should be used at the lowest
dose and for only 2 to 3 nights.
Short-term insomnia lasts from 3 days to 3 weeks and
usually is caused by a personal stressor such as illness, grief, or
job problems. Again, sleep hygiene education is the first step.
Hypnotics may be used adjunctively for 7 to 10 nights.
Hypnotics are best used intermittently during this time, with the
patient skipping a dose after 1 to 2 nights of good sleep.

Long-term insomnia is insomnia that has lasted for more than 3

weeks; no specific stressor may be identifiable. A more complete
medical evaluation is necessary in these patients, but most do not
need an all-night sleep study.
 Classification of Sedative & hypnotic drugs
Benzodiazepines
Hypnotics Anxiolytics
Diazepam Diazepam
Nitrazepam Alprazolam
Lorazepam Oxazepam
Temazepam Lorazepam
Triazolam Flurazepam
Midazolam Chlordiazepoxide

Anti-convulsants
Diazepam
Clonazepam
Clobazepam
2. Non-Benzodiazepine Hypnotics
Zopiclone,Zolpidem, Zaleplon

3. Atypical Anxiolytics-
Buspirone, Ipsapirone, Gepirone

4. β-Adrenergic Antagonists-
Propranolol

5.Barbiturates- Now obsolete,have been superseded by

benzodiazepines
Long Acting Short Acting Ultra-short Acting
Phenobarbital Pentobarbital Thiopental
Mephobarbital Secobarbital Methohexital
Amobarbital
BENZODIAZEPINES-difference with Barbiturates
●They do not provide anesthesia even in higher doses.
●These are not enzyme inducers & hence do not lead
to metabolic tolerance.
●BZDs have a very low abuse liability.
●BZDs do not affect REM sleep and cause lesser
distortion of normal hypnogram.
●BZDs show no hyperalgesia.
●Hypnotic doses of BZDs do not affect respiration or
cardiovascular functions.
 Site of Action:
LIMBIC SYSTEM,MIDBRAIN Ascending RAS,some actions on
medullary site & cerebellum.

Mechanism of Action:
Normally a balance between excitatory inputs(mostly Glutaminergic) and
the inhibitory inputs( mainly GABAergic) determines the prevailing level
of neural activity in limbic system and RAS of the brain.
GABA receptors: GABAA & GABAB

● GABAA receptors located postsynaptically, of which causes

hyperpolarization & directly linked with Cl- ion channels,opening
reduction in membrane excitability.
•GABAB receptors which are GPCRs.
•Their activation decreases cAMP formation.
•They cause pre- and postsynaptic inhibition by
inhibiting Ca+ channel opening &
increasing K+ conductance.
◙
GABAA receptor has several binding sites:-
-The neurotransmitter GABA-binding site.
-The modulatory sites to bind BZDs, their
antagonists like Flumazenil and inverse agonists such
as β-carbolines.
-The modulatory as well as blocking site at Cl- ion
channel.
GABA A receptors are the target for several imp.
centrally acting drugs like
BZDs,Barbiturates,Neurosteriods and Picrotoxin.
BZDs which have powerful SEDATIVE and
ANXIOLYTIC effects, selectively bind, with high
affinity, to the Modulatory site on GABA A receptor in
such a way that the binding of GABA to GABAA receptor
is facilitated.
This modulatory site of GABA A receptor is
DISTINCT from the GABA BINDING SITE, referred as
“BZD receptor”.
BZDs neither substitute for GABA, nor activate
GABAa receptor but rather enhance binding of GABA to
the GABA binding site.
They appear to increase the Frequency (rather the
Duration) of GABA gated chloride channel opening.
BZD Inverse Agonists, Antagonists and Diazepam-
Binding Inhibitor :

Endogenous decapeptide called “diazepam binding

inhibitor” has been isolated from rat brain.
It inhibits Cl- channel opening by GABA.
Agonists like diazepam facilitate,
while inverse agonists like β-carbolines hinder
GABA mediated Cl- channel opening.

BZD Antagonist- Flumazenil, used clinically to

reverse BZD anesthesia and BZD overdose.
PHARMACOKINETIC CHARACTERISTICS:
-Variable oral absorption.
-Cross placental barrier
-More than 90% plasma –protein binding.
-No significant drug displacement reaction-d/t marked
redistribution.
-Most BZDs undergo microsomal oxidation(phaseI reaction).
-BZDS may be catagorised according to their PK characteristics---
ULTRA-SHORT ACTING BZDs:
Triazolam(t1/2 2-4 hrs),good for sleep induction(b’coz of faster
action).No active metabolite.Rebound insomnia may occur.
Midazolam(t1/2 2-4 hrs),duration of action≤6 hrs,active
metabolite,mainly used as I.V. inducing agent in anesthetic practice.
It also causes amnesia.
SHORT-ACTING BZDs:
Lorazepam(t1/2 10-20 hrs),used IV for pre-anesthetic medication.
Oxazepam(t1/2 6-20 hrs).
Temazepam (t1/2 10-20 hrs).
INTER-MEDIATE ACTING:
Alprazolam(t1/2 10-15 hrs)
Nitrazepam (t1/2 20-30 hrs).
LONGER ACTING BZDs:
Chlordiazepoxide(t1/2 10-30 hrs)
Diazepam(t1/2 20-60 hrs),actve metabolite-nordiazepam &
oxazepam.
Flurazepam(t1/2 40-80 hrs)
Clonazepam(t1/2 18-50 hrs)
Therapeutic uses:
1) To treat anxiety neurosis- Lorazepam, preferred for short-lived
anxiety states, compulsive-obsessive neuroses and tension
induced psychosomatic symptoms(dose 1-6 mg /day).It is the
only suitable BZD for PARENTERAL use.
2) Other drugs used- Oxazepam, Diazepam. Chlordiazepoxide for
chronic states.

3) To treat insomnia- BZDs are hypnotic drugs of choice.

Transient insomnia-rapidly acting drugs- Triazolam(0.125-0.25mg
HS),Temazepam.
Short-term insomnia:Temazepam(15-30mg,HS),or Flurazepam(15-30
mg,HS).
Long-term chronic insomnia:Flurazepam(15-30mg hs) or
Nitrazepam(5-10mg,hs) are preferred because Rebound insomnia and
withdrawal effects are less marked with these drugs.

4)For preanesthetic medication & induction of Anesthesia:

Diazepam,lorazepam & midazolam are generally used.
5) As Skeletal muscle relaxants :Diazepam is the preferred for the
relaxant effects in skeletal muscle spasticity of central origin.
6)As Anti-convulsants- Diazepam and clonazepam (slow i.v) are used
to treat status epilepticus.,to prevent tetanic spasm.
7)Treatment of alcohol withdrawal: Diazepam,oxazepam &
chlordiazepoxide are commonly used.
Adverse Effects:
-High margin of safety.
-Tolerance to sedative effects develops slowly .
-Dependence to BZDs is mild.Abuse liability is low.

Mechanism of Dependence- gradual decline in the Functional GABA

activity resulting from down-regulation of GABA receptor after their
prolonged use.

BZD withdrawal includes- anxiety, insomnia, impaired concentration,

headache, irritability,tremors,palpitation and vivid dreams.

Flunitrazepam-tasteless BZDs, misused b’coz of sedative-amnestic

effects, in sexual assaults or so called “date rapes”.
Benzodiazepine antagonist (Flumazenil)
It binds competitively with high affinity and antagonizes
the binding of BZDs.
Shows first pass effect on oral administartion
After parenteral administration ,it enters the brain and
max conc. is achieved within 5-10 mins.
flumazenil has been employed in:
1) Reversing the BZD toxicity
2) Also tried in hepatic coma and acute alcohol
intoxication.
 Dosage-
A dose of 1mg of flumazenil given over 1-3
minutes abolishes the effects of therapeutic doses
of BZDs.
Drug interactions:
-BZDs potentiate the effects of other CNS
depressants(alcohol,hypnotics & neuroleptics).
-Smoking decreases the activity of BZDs.
-Enzyme inhibitors(cimetidine,ketoconazole) enhance BZD
action.
NON-BENZODIAZEPINE HYPNOTICS
Two types of BZD receptor: Type1(BZ1 or ω1
receptor)-throughout brain & large conc.in cerebellum.
Responsible for anti-anxiety,sedative and hypnotic
action.
Type2 (BZ2 or ω2) found mainly in cerebral
cortex,hippocampus, and spinal cord.They are responsible
for muscle relaxation, anti-convulsant action and
amnesia.
Non-BZDs Zolpidem(t1/2 2-3 hr),zopiclone(t1/2 6-8 hrs)
and zaleplon(t1/2 3-4 hrs) act on BZ1 receptor only.
In therapeutic doses they hardly alter REM sleep pattern with
minimal day time residual sedation, minimal rebound
insomnia.

Zolpidem(10-20mg,hs) and Zaleplon(10-20mg,hs) –for

transient insomnia.

Zopiclone(7.5 mg,hs) –short-term insomnia.

Side effects and safety are same as BZDs.

Headache,day time drowsiness and nightmares with higher
doses.
ATYPICAL ANXIOLYTICS:
Buspirone,Ipsapirone and Gepirone--------
-Act through non-GABA ergic systems,
-Low propensity of S/E.
- Used for mild-to- moderate generalized anxiety.
-ineffective in severe cases.
MOA: Selective activation of the inhibitory pre-synaptic 5-HT1A
receptor, they suppress 5-HT neurotransmission.

-Does not interact with BZD receptor or modify GABAergic

transmission.
-Biological lag phase- 2 weeks, not suitable for acute anxiety.
-No muscle relaxant, or anti-convulsant or hypnotic action.
-Minimal abuse liability/does not produce tolerance or physical
dependence.
-Lesser impairment of psychomotor skills.
- Does not potentiate the CNS depressant effects of ethanol.
β-Adrenergic Antagonists:
Propranolol: block sympathetic overactivity

Barbiturates:
MOA: act on the channel modulatory site of GABAA receptor and
potentiate the GABAA mediated inhibitory effects by increasing the
DURATION of Cl- channel opening.
At higher conc, barbiturates directly increase Cl- ion conductance, i.e.
they exhibit a GABA mimetic not facilitatory.

Classification:
Classified according to the duration of action— lipid solubility
--PK characteristics.
Ultra-short acting : thiopental,methohexital(DOA -15-20min).
Short-acting : pentobarbital,secobarbital and amobarbital(DOA 3-8hrs)
Longer-acting : Phenobarbital and mephobarbital(anticonvulsant
drugs).
PK:
Rate of absorption depends on their lipid solubility.
-Sodium salts are alkaline,therefore cannot be given
I.M/S.C inj for fear of necrosis.
These are slightly acidic drugs.
-Redistribution
-metabolise by phaseI and phase-II process.
-alkalization increase their excretion.
Pharmacological Effects:
Dose dependent sedation→hypnosis→GA→coma.
Anti-convulsant action has NO relation with sedative action.
Disrupt the balance between REM:NON-REM by decreasing the
duration of REM sleep.
Hyperalgesic action.
sedative –hypnotic doses have no effect on CVS parameters.High
doses decrease BP,HR & depress myocardium.
higher doses depress respiration.-cause shallow breathing &
Chenye –Stokes rhythm,pulmonary edema,laryngeal edema.
Prolonged use increases the size and weight of smooth E.R
leading to enzyme induction.
Therapeutic Uses:
1) As sedative hypnotics.
2) In GA.
3) As anti-convulsant.
4) Diagnostic aid in psychoanalysis.
5) To treat hyperbillirubinaemia of neonates.,as they increase the
activity of Glucuronyltransferase enzyme by enzymatic induction.
Adverse Effects:
1) metabolic tolerance.
2) Abuse liability.
3) Hangover,impairment of judgement and” “ drug automatism.
4) Respiratory depression,laryngeal oedema and hypersensitivity
reactions.
Drug Interactions:
Induce metabolism of OCPs,anticoagulants,tolbutamide and
theophylline.
Contraindications:
•Liver dysfunction,kidney disease,severe pulmonary
insufficiency, family H/O porphyria/acute intermittent
porphyria- B’coz barbiturates cause induction of ALA-
synthase enzyme in mitochondria.
•This leads to increased synthesis of porphyrins and hence
porphyria and neurotoxicity.
Miscellaneous drugs:
Hydroxyzine: is an antihistaminic having anti-
emetic,sedative, anticholinergic,& LA.
Also used for pre-anesthetic medication, pruritus,anxiety.
Promethazine:
Sedative anti-histaminic with anti-emetic anti-cholinergic
activities.(popularly in children).
 Melatonin:
A hormone produced in pineal gland from Aminoacid
tryptophan.
-diurnal rhythm of secretion.
-acts as chronobiotic
-used to t/t jet lag & disorders of delay in sleep induction.
PK:
-Bioavailability variable.
-very first pass metabolism.
-excreted mainly in kidneys.
Thank you