This document discusses sedatives and hypnotics. It defines sedatives as drugs that reduce excitement and produce calming effects without inducing sleep, while hypnotics produce sleep resembling natural sleep. Both act through GABA receptors in the brain. Common classes discussed are benzodiazepines, which potentiate GABA receptors, and barbiturates, which directly activate chloride channels. Specific drugs are described along with their mechanisms, effects, uses, and toxicity risks. Sleep cycles and how different drug classes impact sleep stages are also outlined.

1. Prepared
By
Dr.Hariprasad MG
Professor and HOD
Department of Pharmacology, KLE College of
Pharmacy
Bangalore
1

2. Sedatives & Hypnotics
Sedatives
 A drug that reduces excitement,
produces calming or quietining
effect and may induce sedation
(without inducing sleep)
 Sedatives in therapeutic doses are
anxiolytic agents (Reduces anxiety)
 Site of action is on the limbic
system which regulates thought and
mental function
Hypnotics
 A drug which produces sleep
resembling natural sleep
 They are used for initiation and /
or maintenance of sleep.
 Hypnotics in higher doses
produce General anesthesia.
 Site of action is on the midbrain
and ascending RAS(reticular
activating system) which maintain
wakefulness.
Sedative and hypnotics also have
these actions
Antianxiety
Anticonvulscent
Preanesthetic medication
Potentiate analgesic action
Adjuvant to anasthesia
Muscle relaxation and amnesia
Sleep is defined as a natural and
reversible state of reduced
responsiveness to external stimuli
and relative inactivity, accompanied
by a loss of consciousness
Sleep consists of two phases
2

3. Sedatives & Hypnotics
Non rapid eye ball movement(NREM)
• Very peaceful
• Parasympathetic activity is more
• Increased acetylcholine release
• Decreased metabolic rate, heart rate,
cardiac output
• Dreaming is infrequent and rarely recalled
has following stages
• Stage 1:
• Slow eye ball movements
• Muscle tone throughout the body relaxes
• Stage 2:
• The slow moving eye rolls discontinue
• Body temperature begins to decrease and
heart rate begins to slow.
• Stage 3:
• Parasomnias (sleepwalking, sleep talking)
occurs
• Growth hormone secreted
• Contributes for physical growth and
development
Rapid eye ball movement(REM0
• After about 90-120 minutes of
NREM sleep, REM sleep occurs
lasting for 5-30 minute
• Not so restful
• Sympathetic activity is more
• Increased release of adrenalin and
nor adrenaline
• Increase heart rate and blood
pressure.
• Eye movements are rapid, moving
from side to side
• heart rate and breathing quickens
• Intense dreams,75% of dream
occurs in this phase
• Contributes to memory
consolidation
3

4. Classification
Benzodiazepines
• Short acting(2-5 h)
• Triazolam
• Oxazepam
• Midazolam
• Intermediate
acting(10-24h)
• Alprazolam
• Estazolam
• Lorasepam
• Nitrazepam
• Long acting(20-50 h)
• Diazepam
• Flurazepam
• Clonazepam
• Chlordiazepoxide
• Non benzodiazepines(Z
drugs)
• Zolpidem
• Zopiclone
• Zaleplon
Barbiturates
• Long acting
• Penobarbitone
• Methobarbitone
• Intermediate
• Amobarbitone
• Butobarbitone
• Short acting
• Pentabarbitone
• Secobarbitone
• Ultra short acting
• Thiopentone
• Methohexitone
• Non barbiturates
• Chloralhydrate
• Paraldehyde
Miscellaneous
• Miscellaneous
• Melatonin receptor
agonist
• Ramelteon
• Melatonin
• Carbamate derivatives
• Meprobamate
• Non Carbamate
derivatives
• Glutethimide
• Others
• Antidepressants
• Dpxepin
• Mirtazapine
• Trazodone
• Antihistaminics
• Hydroxyzine
• Cyprohepatadin
4

5. Benzodiazepines
They bind to specific site on GABA A – BZD receptor Cl channel
complex.
They exert their action only in the presence of GABA – for this reason
they are called positive allosteric modulators (PAMs)
Benzodiazepines are Positive Allosteric Modulators(PAMs) of GABA-A
Receptors(Ligand gated ion channel or inotropic receptors)
Benzodiazepines acts as GABA potentiators. GABA is the main
inhibitory neurotransmitter in the brain
Increase binding of GABA to GABAA receptor thus increase
frequency of chloride channel opening
Hyperpolarization of nerve membrane
Inhibitory effect on CNS
Increase chloride conductance
Benzodiazepines are Non-selective and bind to GABA-A alpha subunits.
Each of these subunits is associated with different
effects:α1:Sedation,amnesia,partial anticonvulsant ,alcohol potentiating
actions,α2:Anxiolysis,Myorelaxation α3&5:Myorelaxation,ataxia
Fig 1.GABA A: Pentameric transmembrane
anion channel:five subunits a555, b, g and
also d, e, p, r, etc.But (α1)2,(β2)2 & (γ2)1
subunits – most commonly expressed BZD
receptor isoform
5

6. Site of action,agonist,antagonist
Site of action Molecular pharmacology of the GABA receptor
6
Ligand Subunit
GABA β
Barbiturate α or β
Benzodiazepine α /γ interface
Z-drugs α 1
Site action
Midbrain ( RAS ) Wakefulness
Limbic system Thought & mental
functions
Muscle
relaxation
Muscle relaxation
Cerebellum Ataxia
Agonist Antagonist Inverse agonist
GABA: Promotes Chloride influx
Barbiturates: Facilitates & mimics
GABA action
Benzodiazepines: Facilitate GABA
action
Alcohol, Inhalational anaesthetics,
propofol: open Cl- channel directly
Bicuculline: competitive
antagonist at GABA Rc
Flumazenil: competitive
antagonist at BZD site
Picrotoxin: blocks Cl-
channel non-competitively
Inverse agonists at
BZD site: b-carbolines
(DMCM –
dimethoxyethyl-
carbomethoxy-b-
carboline):
produce anxiety and
seizures
GABAA Receptor chloride Channel binding site ligands

7. Pharmacological actions
• Therapeutic dose ⇒ Anxiolytic > Sedative
• Higher dose ⇒ Depress RAS → Sedative & hypnotic effect
• Dose dependent action: Sedation → Hypnotic → Anesthetic → Coma → Death
 Anxiolytic effect: At low doses, the benzodiazepines are anxiolytic – reduce anxiety
by selectively enhancing GABAergic transmission in neurons having the α2 subunit
in their GABAA receptors – thereby inhibiting neuronal circuits in the limbic
system of the brain – The antianxiety effects of the benzodiazepines are less subject
to tolerance than the sedative and hypnotic effects.
 Sedative/hypnotic effect: All benzodiazepines have sedative and calming properties
• Some can produce hypnosis (artificially produced sleep) at higher doses
• The hypnotic effects are mediated by the α1- GABAA receptors
 Anticonvulsant effect: Several benzodiazepines have anticonvulsant activity. This
effect is partially, although not completely, mediated by α1-GABAA receptors.
 Muscle relaxant effect: At high doses, the benzodiazepines relax the spasticity of
skeletal muscle by increasing presynaptic inhibition in the spinal cord, where the
α2-GABAA receptors are largely located
7

8. Pharmacological actions
• Produce centrally mediated skeletal muscle relaxation without impairing
voluntary activity
• Very high dose depress neuromuscular transmission
 Anterograde amnesia: Temporary impairment of memory with use of the
benzodiazepines
• Mediated by the α1-GABAA receptors.
• The ability to learn and form new memories is also impaired.
• Anesthetic effect:
 Dependence: Psychological and physical dependence can develop if high
doses are given for a prolonged period.
• Abrupt discontinuation results in withdrawal symptoms – confusion, anxiety,
agitation, restlessness, insomnia, tension, and (rarely) seizures
• Benzodiazepines with a short elimination half-life, such as triazolam, induce
more abrupt and severe withdrawal reactions than those seen with drugs that
are slowly eliminated such as flurazepam
• Other effects: Decrease blood pressure and respiratory rate
• Decrease nocturnal gastric acid secretion
• Mild respiratory depression and hypotension at high doses
8

9. Pharmacokinetics
 Pharmacokinetics :
• Well absorbed after oral administration (stomach &small intestine) and
distribute throughout the body.
• Distribution and Duration of action determined by lipid Solubility – More lipid
soluble = fast onset & short duration of action, but… – sequestered by body fat
– and as brain levels fall, released slowly from fat cells back into blood
• Metabolized in liver by dealkylation, hydroxylation and again converted into
active metabolite
• Metabolites are excreted in urine as glucorunide conjugates
• Can cross placenta and secreted in milk.
 Adverse Effects: Drowsiness and confusion, Most common are Ataxia
occurs at high doses
• Cognitive impairment (decreased long-term recall and retention of new
knowledge)
• Benzodiazepines should be used cautiously in patients with liver disease.
• Alcohol and other CNS depressants enhance the sedative–hypnotic effects of
the benzodiazepines.
• Administration in third trimester can result in “floppy-infant syndrome” (a
state of low muscle tone) 9

10. Therapeutic Uses:
Therapeutic Uses:
 Anxiety disorders: Benzodiazepines are effective for the treatment of the
anxiety symptoms secondary to panic disorder, generalized anxiety
disorder (GAD), social anxiety disorder, performance anxiety,
posttraumatic stress disorder, obsessive–compulsive disorder, and
extreme anxiety associated with phobias and anxiety related to
depression and schizophrenia.
 The longer-acting agents, such as clonazepam, lorazepam, and
diazepam, are often preferred in those patients with anxiety that may
require prolonged treatment.
 For panic disorders, alprazolam is effective for short- and long-term
treatment
 To control Alcohol withdrawal symptoms: chlordiazepoxide, diazepam &
oxazepam
 Sleep disorders:
 Insomnia:Decrease the latency to sleep onset and increase stage II of non–
rapid eye movement (REM) sleep. 10

11. Therapeutic Uses:
 Both REM sleep and slow-wave sleep are decreased.
 Commonly prescribed benzodiazepines for sleep disorders include
intermediate-acting temazepam and short-acting triazolam.
 Long-acting flurazepam is rarely used, due to its extended half-life, which
may result in excessive daytime sedation
 Amnesia: The shorter-acting agents are often employed as pre- medication for
anxiety-provoking and unpleasant procedures, such as endoscopy, dental
procedures, and angioplasty.
 Midazolam is used to facilitate amnesia while causing sedation prior to
anesthesia.
 Seizures: Clonazepam is used as an adjuvant therapy for certain types of
seizures
 Lorazepam and diazepam are the drugs of choice in terminating status
epilepticus.
 Due to cross-tolerance, chlordiazepoxide,diazepam, lorazepam, and oxazepam
are useful in the acute treatment of alcohol withdrawal and reduce the risk of
withdrawal-related seizures
 Muscular disorders: Diazepam is useful in the treatment of skeletal muscle
spasms, such as occur in muscle strain spasticity from degenerative disorders,
such as multiple sclerosis and cerebral palsy
11

12. Drug interactions
 Drug interactions:
• Concomitant use of benzodiazepines and opioids may result in profound
sedation, respiratory depression, coma, and death.
• Phenothiazines, opioids, barbiturates, monoamine oxidase (MAO)
inhibitors,antidepressants,alcohol illicit drugs like heroin (an opiate)
produce additive effect on the central nervous system depression if
combined with benzodiazepines.
• CYP3A4 inhibitors such as clarithromycin, ketoconazole and ritonovir
may rise levels of the benzodiazepine
12

13. Z-drugs
 Z-drugs:
Zolpidem, Zaleplone, Zopiclone
• These are not structurally related to benzodiazepines, but selectively
bind to the benzodiazepine receptor sub- type BZ1.
• Do not significantly alter the various sleep stages and, hence, are often
the preferred hypnotics
• No anticonvulsant or muscle-relaxing properties.
• Shows few withdrawal effects, exhibits minimal rebound insomnia, and
little tolerance occurs with prolonged use
• Other effects are similar to benzodiazepines
13

14. Benzodiazepines
Diazepam Flurazepam Alprazolam
It is used to control convuslion but not for
longterm therapy of epilepsy because of
sedative
effect and rapid development of toleranc
e to the anti convulsant effect
It produces active metabolites that ha
ve long plasma half lives, hence cumm
ulative effects may be seen with
repeated doses
It is short acting BZD.
In addition to antianxiety action, it a
lso have antidepressant effect
Midazolam
It is short acting benzodiazepines with
potent amnesic effect. It is mainly us
ed i.v. anesthetics in minor surgical proc
edures
Lorazepam:
It is short acting BZD with antianxie
ty, anticonvulsant, sedative and amnesic
effects.
Chlordiazepoxide
has a medium to long hal life but its
active metabolite has a very long half-
life.
The drug has amnesic, anticonvulsant
,anxiolytic ,hypnotic, sedative and
skeletal muscle relaxant properties.
14

15. Benzodiazepine toxicity
15
Benzodiazepine toxicity: benzodiazepine overdose may have the following
signs and symptoms
Dizziness, inability to talk or respond, confusion, drowsiness, burred
vision or nystagmus, agitation, weakness, low blood pressure, respiratory
depression, hallucinations, coma
Flumazenil: is used to reverse the sedative effect of a benzodiazepine when
used for a medical procedure and for treatment in a benzodiazepine overdose
MOA: A selective competitive antagonist of BZD receptors (BZ-1). Blocks
action of Benzodiazepines and Z- drugs but not other sedative /hypnotics.
Uses: Acute BZD toxicity – reversal of BZD sedation e.g. after endoscopy

16. Barbiturates
Barbiturates :Derivatives of baribituric acid which is condensation product
of urea with malonic acid
MOA:
 Barbiturates bind to wither α or β subunit of benzodiazepine receptor
chloride complex
 Increase duration of opening of Cl- channels induced by GABA (GABA
facilitatory action)
 At high concentration
 Can directly increase Cl- conductance through Cl- channels (GABA
mimetic action)
 Inhibit Ca2+ dependent release of neurotransmitters
 Depress glutamate induced neuronal depolarization through AMPA
receptor
 At very high concentration (anaesthetic doses)
 Depress voltage sensitive Na+ & K+ channels
16

17. Pharmacological actions
Pharmacological actions:
 CNS: Depress CNS in dose dependent manner
Low dose: Sedative
High dose: Hypnosis
Still higher doses: Anesthesia
 Sedation and hypnosis: Induce sleep similar to natural sleep
Compare to benzodiazepines
Exhibit hangover
Ineffective in pain
Decrease REM phase, increase dreaming and motor incordination
Chance of drug abuse is high
 Anaesthetic: Ultra short acting barbiturate by IV route produce general anaesthesia
 Anticonvulsant and antiepileptic: Acts as anticonvulsant due to its depressant
action on reticular formation and increasing GABA action
 Analgesic action: Barbiturates do not raise the pain threshold and have no
analgesic properties. But enhance the analgesic effect of NSAIDS when given in
combination
 Respiration: Barbiturates suppress the hypoxic and chemoreceptor response to
CO2, and over dosage is followed by respiratory depression and death.
• Large dose cause circulatory collapse due to medullary vasomotor depression &
direct vasodilatation. The overall effect is due to neurogenetic ,chemical drive and
hypoxic drive. 17

18. Pharmacological actions
 CVS: In hypnotic dose, heart rate and blood pressure are decreased. In toxic
doses ,suppress cardiac center and cause circulatory collapse
 GIT: Do not affect motility of gut significantly
 Kidney: Barbiturates decreases glomerular filtration rate and causes release of
ADH leading to urinary retention and decrease urine output
 Liver: Barbiturates in acute dose inhibit action of CYP450 system and inhibit
metabolism of other drugs
 Chronic administration activate or induce CYP 450 system and inactivate the
drugs by enhancing metabolism of drugs
Pharmacokinetics:
 Weak acid so mostly absorbed from stomach and also exhibit satisfactory
absorption from intestine and rectum. All barbiturates redistribute from the
brain to the splanchnic areas(viscera or internal organs), to skeletal muscle,
and, finally, to adipose tissue.
 CNS effects of thiopental are terminated by rapid redistribution of the drug
from the brain to other highly perfused tissues (skeletal muscles) readily cross
the placenta and can depress the fetus.
 Metabolized in the liver, and inactive metabolites are excreted in urine.
Alkalinization increases excretion (NaHCO3)
18

19. Pharmacological actions
Adverse effects:
• Intolerance: excitement, headche,nausea,vomiting
• Barbiturates induce cytochrome P450 (CYP450) microsomal enzymes in the liver.
Therefore, diminishes the action of many drugs that are metabolized by the CYP450
system.
• Barbiturates are contraindicated in patients with acute intermittent porphyria (because
of increased heme synthesis). Increase activity of hepatic gamma amino levulinic acid
synthetase ALA synthesis of porphyrin
• Chronic use results in development of tolerance: Metabolic tolerance Occurs with
phenobarbital -Induces its own metabolism (Self inducer)
• Decreases CNS response to the drug itself
• Abrupt withdrawal from barbiturates may cause tremors, anxiety, weakness,
restlessness, nausea and vomiting, seizures, delirium, and cardiac depression –
Death may also result from overdose
• Depression of fetal respiration: Contraindicated to pregnant women as it cross placenta
and cause fetal depression
• Drug automatism: While taking as hypnotic due to amnesia and confusion, repeated dose
leads to self poisoning
• Drug tolerance and drug dependency: Repeated administration lead to tolerance due to
enzyme induction and addiction (CNS depressant)
19

20. Therapeutic Uses
Therapeutic Uses:
 Sedative/Hypnotic: Barbiturates have been used as mild sedatives to relieve
anxiety, nervous tension, and insomnia.
 However, the use of barbiturates for insomnia is no longer generally accepted, due
to their adverse effects and potential for tolerance.
 General anesthesia (GA): The ultra short acting barbiturates ( thiopentone and
methohexitone ) are used in induction of GA. but have largely been replaced by
other agents.
 Anticonvulsant: Phenobarbitone has anticonvulsant effect and used in treatment
of status epilepticus and generalized tonic- clonic seizures ( GTCS , grand mal
epilepsy )
 Hyperbilirubinemia, neonatal jaundice and non hemolytic type and
kernicterus: (is a rare kind of preventable brain damage that can happen in
newborns with jaundice) in the neonates (increase glucouronyl transferase
activity).and hastens the metabolism of bilurubin.
 Diagnostic aid and Psychiatry: i.v. thiopentone in subanesthetic dose produces a
state of deep sedation. The patient becomes more communative, which helps in
diagnostic of psychiatric disorders like histeria(uncontrolled laughing and crying)20

21. • Drug interactions:
• Barbiturates may decrease the effectiveness of hormonal birth control such
as pills, patch, or ring. This could cause pregnancy.
• Concurrent use of divalproex sodium or valproic acid may decrease the
metabolism of barbiturates, resulting in increased serum concentrations,
which may lead to increased CNS depression and neurological toxicity;
• Chronic use of barbiturates prior to enflurane, halothane,
or methoxyflurane anesthesia may increase anesthetic metabolism leading
to increased risk of hepatotoxicity.
21

22. Comparison of Benzodiazepines and Barbiturates
Benzodiazepines Barbiturates
Less neuronal depression o High therapeutic
index
More neuronal depression
Low margin of safety
No anaesthesia even at high doses
Patient can be aroused
Loss of consciousness
No effect on respiration or cardiovascular
functions at hypnotic doses
Cause respiratory and cardiac depression
No effect on REM sleep
Less distortion of normal hypnogram
++ suppression of REM sleep
Withdrawal ⇒ rebound ↑ in sleep Hangover
Abuse liability very low Tolerance
Dependence
Amnesia without automatism Amnesia with automatism
Loss of short term memory
Not enzyme inducers – Less drug interactions Potent enzyme inducers – More drug
interactions
Specific antagonist – Flumazenil No antagonist available
22

23. Barbiturate toxicity
Signs and symptoms
 Slurred speech, ataxia, lethargy, confusion, headache,nystagmus.
 CNS depression, coma, shock.
 Pupils are at first constricted, but later dilate because of hypoxia.
 Hypothermia.
 Cutaneous bullae (“barb burns”, barbiturate blisters): These are clear, erythematous
or haemorrhagic blisters, and occur in various areas of the body.
 Death may occur from respiratory arrest or cardiovascular collapse.
 Chronic barbiturate (ab)use is associated with the development of tolerance which is
responsible for decreasing the therapeutic to toxic index.
Diagnosis
1. Serial plasma levels may be useful in the management of phenobarbitone
overdose. Plasma levels exceeding 8 mg/dL (80 mcg/mL) (344 mcmol/L) are
generally associated with some degree of coma.
2. EEG: alpha coma indicates poor prognosis. (Alpha coma, an
electroencephalogram (EEG) pattern, characterized by a diffuse or widespread
rhythmic activity in the alpha frequency band, is typically recorded in patients with
profound coma 23

24. Treatment
• Immediate hospitalization
• Attention to ABC(Airway, Breathing and Circulation)
 Gastric lavage: If the patient is conscious then vomiting by giving emetics
• If the patient is unconscious simple aspiration of gastric content
 Endotracheal intubation: Adequate ventilation is important if respiration is
inadequate and also remove secretions
 Monitor CBC (complete blood count), serum electrolytes, glucose, blood urea
nitrogen, creatinine, and urine myoglobin in patients with significant
intoxication.
• Multiple dose activated charcoal has been shown to greatly increase
phenobarbitone elimination
• Forced alkaline diuresis is said to be particularly useful in phenobarbitone
poisoning
 Haemodialysis: Barbiturate elimination can be increased by haemodialysis or
charcoal haemoperfusion.
 Supportive measures: Supplemental oxygen, intubation, assisted ventilation,
IV fluids should be given
• IV fluid: Fluid should be given sufficiently in forced diuresis to prevent
dehydration
 Prophylactic antibiotics: To prevent ventilation associated pnemonia &
hospital acquired infection, during mechanical ventilation
24

25. Non barbiturates
Chloral hydrate: Chloral hydrate and its metabolite trichlorethanol acts a
hypnotic
• Chloral hydrate is for short-term use as a sedative
• It is safe, effective and cheap
• MOA: Similar to barbiturates
• ADR: Unpleasant taste, skin rashes and nausea
• Chloral hydrate may also be used to treat alcohol withdrawal symptoms, or to
relieve anxiety caused by withdrawal from certain drugs such as barbiturates or
narcotic medicine.
Paraldehyde:
• It is classified as a central nervous system (CNS) depressant and has also been
found to be an effective anticonvulsant, hypnotic and sedative agent
• MOA: Paraldehyde is believed to reduce the release of acetylcholine in
response to neuronal depolarization . The exact mechanism of this effect is
unknown.
• ADR: headache, nausea, drowsiness, unconsciousness, coma, severe
hypotension, respiratory depression, pulmonary edema
25

26. Melatonin receptor agonist,Carbamates
Melatonin receptor agonist:
 Ramelteon and Melatonin
• Selective agonist at the MT1 and MT2 subtypes of melatonin receptors.
• Melatonin is a hormone secreted by the pineal gland that helps to maintain the
circadian rhythm underlying the normal sleep–wake cycle.
• No direct effects on GABAergic neurotransmission
• Indicated for the treatment of insomnia characterized by difficulty falling asleep
(increased sleep latency)
Advantages: No effects on sleep architecture, no rebound insomnia or significant
withdrawal symptoms, minimal potential for abuse, and no evidence of dependence
or withdrawal effects(can be administered for long term)
Carbamate derivatives:
Mepronamate:
• Meprobamate appears as odorless white crystalline powder bitter taste.
Meprobamate is a carbamate derivate with hypnotic, anti-anxiety, sedative,
anticonvulsant and some indirect muscle relaxant properties
• MOA: It appears to act as a depressant at multiple sites in the central nervous
system, mostly likely through the GABAergic neurotransmitter system,
including the thalamus and limbic system.
• ADR: Drowsiness, dizziness,headache, excitement, nausea,vomiting and diarrhoea26

27. Glutethimide
 Glutethimide : Glutethimide is a hypnotic and sedative. Its use
has been largely superseded by other drugs.
• Glutethimide, like the barbiturates, is a hypnotic sedative. It was
introduced in 1954 as a safer alternative to barbiturates but was soon
determined to be just as likely to cause addiction and withdrawal
symptoms.
• MOA: Glutethimide seems to be a GABA agonist which helps
induce sedation
27