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Sedative Hypnotic
Dr. Ashutosh Tiwari
PG Resident, IInd Year
Department of
Pharmacology
SAIMS
26/02/15
Sedative (Anxiolytic)
& Hypnotic Drugs
Overview
• Introduction
• Historical Perspectives
• Classification: Sedative / Hypnotics
• Mechanism of action
• Barbiturates
• Benzodiazepines
• Miscellaneous Hypnotics & Anxiolytics
Introduction
Sedative – Hypnotics
Sedative
• A drug that reduces
excitement, calms the patient
(without inducing sleep)
• Sedatives in therapeutic doses
are anxiolytic agents
• Most sedatives in larger doses
produce hypnosis (trans like
state in which subject
becomes passive and highly
suggestible)
• Site of action is on the limbic
system which regulates
thought and mental function.
Hypnotic
• A drug which produces sleep
resembling natural sleep
• They are used for initiation
and / or maintenance of sleep.
• Hypnotics in higher doses
produce General anaesthesia.
• Site of action is on the
midbrain and ascending RAS
which maintain wakefulness.
Anxiolytic
• Anxiety is an unpleasant state
of tension, apprehension, or
uneasiness that arises from
either a known or an unknown
source
• Anxiolytic is an agent which
decreases worriness
manifested as the psychic
awareness of anxiety which is
accompanied with increased
vigilance, motor tension, and
autonomic hyperreactivity.
Stages of Sleep
Stage2
Non REM
67-75%
REM sleep
25-33%
Stage 1
2-5%
Stage 3 & 4
Deep sleep
15-25%
8
• Eyes open – β, Eyes are closed - α wavesAwake
• Dozing, α + θ, disappearance of α – onset of
sleepStage I
• θ + sleep spindles and K complex
• 40- 50% of total sleep time
Stage II
• Appearance of δ wavesStage III
• δ wave predominatesStage IV
• Reappearance of α, low voltage high frequency (Saw
tooth waves)
• 20-30% of total sleep time
REM
N
R
E
M
70-
80%
Of
Total
sleep
time
Slow
wave
sleep
History
History
• Sedatives (before
development of barbiturates)
– Since antiquity, alcohol
beverages and potions
containing laudanum and
various herbals have been used
to induce sleep.
– Morphine was used for quick
management of aggressive
patients
In 1800: most widely used
sedative in asylums
– In 1857: Bromide was the first
agent to be introduced
specifically as a sedative and
soon thereafter as a hypnotic
History
• 1864: Barbiturates were
introduced
– Barbiturates were widely
diverted from medical use
and used on the street in
the 60s where they were
called “downers” and sold
under a variety of different
names.
– Barbiturates had a low
therapeutic index and were
often used for suicide.
Baeyer,
discoverer of
barbiturates
Marilyn Monroe died of barbiturate
overdose in 1962
History
• By 1990s, barbiturates replaced by
benzodiazepines
– 1961: introduction of chlordiazepoxide
– Sternback is credited with the
invention of chlordiazepoxide,
diazepam, flurazepam, nitrazepam,
clonazepam, and trimethaphan
Leo Sternback
History
• Others and Z Drugs
– Methaqualone (Quaalude) and meprobamate
(Miltown) were used in the 60s as “non barbiturate
tranquilizers”.
• 1951: Methaqualone was synthesized in India as an
antimalarial
• 1965: the most commonly prescribed sedative in Britain
• 1972: the sixth-bestselling sedative in the USA
• discontinued in 1985, mainly due to its psychological
addictiveness and recreational use
– Z drugs: now replacing the BDZs; can be targeted to
specific symptoms, insomnia and anxiety.
SEDATIVE-HYPNOTIC DRUGS
SEDATIVE-HYPNOTICS
Benzodiazepines Barbiturates Miscellaneous agents
Short Ultra Anxiolytics:
action action Buspirone
Intermediate Short Antidepressants
action action Hypnotics:
Long Long Z-drugs
action action Antihistaminics
Doxepin
Ramelteon
Barbiturates
Long Acting Short Acting Ultra-short Acting
• Phenobarbitone • Butobarbitone
• Pentobarbitone
• Thiopentone
• Methohexitone
o Epilepsy
o Neonatal jaundice
Anaesthesia
Benzodiazepines
a/c to Duration of Action
Short acting
• Triazolam
• Oxazepam
• Midazolam
Intermediate acting Long acting
• Alprazolam
• Estazolam
• Temazepam
• Lorazepam
• Nitrazepam
• Diazepam
• Flurazepam
• Clonazepam
• Chlordiazepoxide
Benzodiazepines
a/c to Indications
Hypnotic Antianxiety Anticonvulsant
• Diazepam
• Flurazepam
• Nitrazepam
• Alprazolam
• Temazepam
• Triazolam
• Diazepam
• Chlordiazepoxide
• Oxazepam
• Lorazepam
• Alprazolam
• Diazepam
• Lorazepam
• Clonazepam
• Clobazam
Miscellaneous agents
Z Drugs
Melatonin receptor
agonist
Others
• Zolpidem
• Zopiclone
• Zaleplon
• Ramelteon • Antidepressants
• Antihistaminics
Site of Action
• Midbrain ( RAS ) - Wakefulness
• Limbic system - Thought &
mental functions
• Medulla - Muscle relaxation
• Cerebellum - Ataxia
 Effect : Limbic system > Midbrain RAS
⇓
- Therapeutic dose ⇒ Anxiolytic >
Sedative
- Higher dose ⇒ Depress RAS →
Sedative & hypnotic effect
Dose Dependent Action
Sedation
(Sedative)
Sleep
(Hypnotic)
Anesthesia
(Anesthetic)
Coma Death
Dose-response curves for two
hypothetical sedative-hypnotics
• Drug A:
– An increase in dose higher
than that needed for hypnosis
may lead to a state of general
anesthesia.
– With higher doses, the drug
will depress the respiratory
and vasomotor centers which
leads to coma.
– Drug A is an example of
alcohol and barbiturates.
• Drug B:
– needs greater doses to
achieve CNS depression.
– Drug B is an example of
benzodiazepines and newer
hypnotics.
Dose-response curves for two
hypothetical sedative-hypnotics
• Drug A – Barbitutates
– Steeper DRC
– Narrow margin of
safety
• Drug B –
Benzodiazepines
– Flatter dose response
curve
– Greater margin of
safety
Mechanism of Action
MOLECULAR PHARMACOLOGY OF
THE GABA RECEPTOR
• Pentameric transmembrane anion channel
• composed of five subunits a, b, g and also d, e,
p, r, etc.
– there are six different a, four b, and three g
• multiple BZD receptor subtypes
• Two a1 and two b2 and one g2 subunits –
most commonly expressed BZD receptor
isoform
MOLECULAR PHARMACOLOGY
OF THE GABA RECEPTOR
Ligand Subunit
GABA b
Barbiturate a or b
Benzodiazepine a / g interface
Z-drugs a1
GABA-A RECEPTOR Cl CHANNEL
BINDING SITE LIGANDS
• Agonists
– GABA: promotes Cl influx
– Barbiturates: facilitates & mimics GABA action
– Benzodiazepines: facilitate GABA action
– Alcohol, Inhalational anaesthetics, propofol: open Cl channel
directly
• Antagonists
– Bicuculline: competitive antagonist at GABA Rc
– Flumazenil: competitive antagonist at BZD site
– Picrotoxin: blocks Cl channel non-competitively
• Inverse agonists
– b-carbolines (DMCM – dimethoxyethyl-carbomethoxy-b-
carboline): inverse agonist at BZD site
– produce anxiety and seizures
Barbiturates / Benzodiazepines
Bind to GABAA receptor at different allosteric sites
Facilitates GABA action
Barbiturates increase duration &
Benzodiazepines increase frequency
of opening of Cl-
channel
Membrane hyperpolarization
CNS depression
At higher dose
Barbiturates can
act as GABA
mimetic
Mechanism of Action
Mechanism of Action
• Benzodiazepines
 increase frequency of opening of Cl- channels induced by GABA
(GABA facilitatory action)
 increase binding of GABA to GABAA receptor
• Barbiturates
 increase duration of opening of Cl- channels induced by GABA
(GABA facilitatory action)
 at high conc.
 can directly increase Cl- conductance through Cl- channels (GABA
mimetic action)
 inhibit Ca dependent release of neurotransmitters
 depress glutamate induced neuronal depolarization through AMPA
receptor
 at very high conc. (anaesthetic doses)
 depress voltage sensitive Na+ & K+ channels
α γ
α
β
GABA
Bicuculline
Diazepam
Intra cellular side
Flumazenil
DMCM
Barbiturate
GABAA Receptor
Barbiturate receptor
BZD Receptor
Cl--
Picrotoxin
β
Barbiturates
Pharmacokinetics
• well absorbed after oral administration 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
– Two-Phase Excretion Curve – 2 Half-Lives
– Rapid drop in blood level as drug is redistributed;
– Released from body fat;
Pharmacokinetics
• All barbiturates redistribute from the brain to the
splanchnic areas, to skeletal muscle, and, finally, to
adipose tissue.
 CNS effects are 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)
Actions
• At low doses, produce sedation (have a calming effect
and reduce excitement).
• At higher doses, cause hypnosis, followed by
anesthesia (loss of feeling or sensation), and, finally,
coma and death.
• Barbiturates do not raise the pain threshold and have
no analgesic properties
– may even exacerbate pain
• Barbiturates suppress the hypoxic and chemoreceptor
response to CO2, and overdosage is followed by
respiratory depression and death.
• Large dose cause circulatory collapse due to medullary
vasomotor depression & direct vasodilatation.
Therapeutic Uses:
Barbiturates
• Anesthesia:
– The ultra–short-acting barbiturates, such as
thiopental: used IV to induce anesthesia
– but have largely been replaced by other agents.
• Anticonvulsant:
– Phenobarbital is used in long-term management of
tonic–clonic seizures
– can depress cognitive development in children and
decrease cognitive performance in adults, and it
should be used only if other therapies have failed.
– Phenobarbital is used for the treatment of refractory
status epilepticus
Therapeutic Uses:
Barbiturates
• 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.
• Hyperbilirubinemia and kernicterus in the
neonates (increase glucouronyl transferase
activity).
Adverse effects
• drowsiness, impaired concentration, and
mental and physical sluggishness
• The CNS depressant effects of barbiturates
synergize with those of ethanol.
• Hypnotic doses of barbiturates produce a drug
“hangover” that may lead to impaired ability
to function normally for many hours after
waking.
Adverse effects
• 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
Adverse Effects
• Chronic use results in development of tolerance
– Metabolic tolerance
• Occurs with phenobarbital
• Induces its own metabolism
• 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
Benzodiazepines
Pharmacokinetics
• lipophilic
• rapidly and completely absorbed after oral
administration
• distribute throughout the body and penetrate
into the CNS
• Redistribution occurs from CNS to skeletal
muscles& adipose tissue ( termination of
action)
• The longer-acting agents form active metabolites
with long half-lives.
Metabolism
• All Benzodiazepines are metabolized in the liver
– Phase I: ( liver microsomal system)
– Phase II: glucouronide conjugation and excreted in the
urine.
• Many of Phase I metabolites are active: Increase
elimination half life of the parent compound ,
cumulative effect with multiple doses.
• EXCEPTION: No active metabolites are formed for (LEO)
Lorazepam, Estazolam, Oxazepam.
• Cross placental barrier during pregnancy and are
excreted in milk (Fetal & neonatal depression)
Actions
• Reduction of anxiety
– 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.
Actions
• Sedative/hypnotic
– 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.
Actions
• 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.
Actions
• Anticonvulsant
– Several benzodiazepines have anticonvulsant activity.
– This effect is partially, although not completely,
mediated by α1-GABAA receptors.
• Muscle relaxant
– 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.
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
Adverse Effects
• Drowsiness and confusion: Most common AE
• Ataxia occurs at high doses
• Cognitive impairment (decreased long-term
recall and retention of new knowledge) can
occur with use of benzodiazepines.
• 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”
Therapeutic Uses:
Benzodiazepines
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, chlorazepate, diazepam & oxazepam
Sleep disorders
• decrease the latency to sleep onset and increase
stage II of non–rapid eye movement (REM) sleep.
• 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 adjunctive therapy
for certain types of seizures
• lorazepam and diazepam are the drugs of
choice in terminating status epilepticus.
• Due to cross-tolerance, chlordiazepoxide,
clorazepate, 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
Advantages of
benzodizepines over
barbiturates
Benzodiazepines Barbiturates
o Less neuronal depression
o High therapeutic index
o More neuronal depression
o No anaesthesia even at
high doses
o Patient can be aroused
o Loss of consciousness,
o Low margin of safety
o No effect on respiration or
cardiovascular functions at
hypnotic doses
o Cause respiratory and
cardiac depression
o No effect on REM sleep
o Less distortion of normal
hypnogram
o ++ suppression of REM
sleep
o Withdrawal ⇒ rebound ↑
in sleep
o Hangover
Benzodiazepines Barbiturates
o Abuse liability very low o Tolerance
o Dependence
o No hyperalgesia o Hyperalgesia (↑ Sensitivity
to pain)
o Amnesia without
automatism
o Amnesia with automatism
o Loss of short term memory
o Not enzyme inducers – Less
drug interactions
o Potent enzyme inducers –
More drug interactions
o Specific antagonist –
Flumazenil
o No antagonist available
Flumazenil: Benzodiazepine antagonist
• FDA approval in 1991
• 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
Other Anxiolytic Agents
• Antidepressants
– Selective serotonin reuptake inhibitors (SSRIs)
such as escitalopram or paroxetine) or
– serotonin/norepinephrine reuptake inhibitors
(SNRIs), such as venlafaxine or duloxetine
– SSRIs and SNRIs have a lower potential for physical
dependence than the benzodiazepines and have
become first-line treatment for GAD
Other Anxiolytic Agents
• Buspirone
– Acts as a partial agonist at the 5-HT1A receptor
presynaptically inhibiting serotonin release.
• The metabolite 1-PP (1-(2-pyrimidyl-piperazine) has 2 receptor
blocking action
– Indicated for generalized anxiety disorders but takes 1 to 2
weeks to exert anxiolytic effects
– no anticonvulsant or muscle relaxant properties
– Advantages:
• does not have sedative effects and does not potentiate CNS
depressants
• few side effects
• relatively high margin of safety,
• not associated with drug dependence
• No rebound anxiety or signs of withdrawal when discontinued
Other Anxiolytic Agents
• Propranolol ( -blocker)
– Use to treat some forms of anxiety, particularly
when physical (autonomic) symptoms (sweating,
tremor, tachycardia) are severe.
• Clonidine ( 2-Adrenoreceptor Agonists)
– used for the treatment of panic attacks
– useful in suppressing anxiety during the
management of withdrawal from nicotine and
opioid analgesics
Other Hypnotic Agents
• Z-drugs: Zolpidem, Zaleplone, Zopiclone
– not structurally related to benzo diazepines, 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 Hypnotic Agents
• Ramelteon
– 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)
Other Hypnotic Agents
• Antihistamines
– Some antihistamines with sedating properties,
such as diphenhydramine, hydroxyzine, and
doxylamine, are effective in treating mild types of
situational insomnia.
– However, they have undesirable side effects (such
as anticholinergic effects) that make them less
useful than the benzodiazepines and the
nonbenzodiazepines.
Other Hypnotic Agents
• Antidepressants
– Doxepin an older tricyclic agent with SNRI
mechanisms of antidepressant and anxiolytic
action, was recently approved at low doses for the
management of insomnia.
– Other antidepressants, such as trazodone,
mirtazapine and other older tricyclic
antidepressants with strong antihistamine
properties are used off-label for the treatment of
insomnia
Recent Advances
• 5-HT2A receptor antagonists:
– 5-Hydroxytryptamine (5-HT)2A antagonists are
promising therapeutic agents for the treatment of
sleep maintenance insomnias
– unlike hypnotics, they have limited effects on sleep
initiation.
– 5-HT2A antagonists: eplivanserin, volinanserin
• Orexin receptor antagonist
– Orexin is believed to be responsible for maintaining
wakefulness
– Suvorexant, Elmorexant
THANK YOU
66
Sedative Hypnotic

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Sedative Hypnotic

  • 2. Dr. Ashutosh Tiwari PG Resident, IInd Year Department of Pharmacology SAIMS 26/02/15 Sedative (Anxiolytic) & Hypnotic Drugs
  • 3. Overview • Introduction • Historical Perspectives • Classification: Sedative / Hypnotics • Mechanism of action • Barbiturates • Benzodiazepines • Miscellaneous Hypnotics & Anxiolytics
  • 5. Sedative – Hypnotics Sedative • A drug that reduces excitement, calms the patient (without inducing sleep) • Sedatives in therapeutic doses are anxiolytic agents • Most sedatives in larger doses produce hypnosis (trans like state in which subject becomes passive and highly suggestible) • Site of action is on the limbic system which regulates thought and mental function. Hypnotic • A drug which produces sleep resembling natural sleep • They are used for initiation and / or maintenance of sleep. • Hypnotics in higher doses produce General anaesthesia. • Site of action is on the midbrain and ascending RAS which maintain wakefulness.
  • 6. Anxiolytic • Anxiety is an unpleasant state of tension, apprehension, or uneasiness that arises from either a known or an unknown source • Anxiolytic is an agent which decreases worriness manifested as the psychic awareness of anxiety which is accompanied with increased vigilance, motor tension, and autonomic hyperreactivity.
  • 7. Stages of Sleep Stage2 Non REM 67-75% REM sleep 25-33% Stage 1 2-5% Stage 3 & 4 Deep sleep 15-25%
  • 8. 8 • Eyes open – β, Eyes are closed - α wavesAwake • Dozing, α + θ, disappearance of α – onset of sleepStage I • θ + sleep spindles and K complex • 40- 50% of total sleep time Stage II • Appearance of δ wavesStage III • δ wave predominatesStage IV • Reappearance of α, low voltage high frequency (Saw tooth waves) • 20-30% of total sleep time REM N R E M 70- 80% Of Total sleep time Slow wave sleep
  • 10. History • Sedatives (before development of barbiturates) – Since antiquity, alcohol beverages and potions containing laudanum and various herbals have been used to induce sleep. – Morphine was used for quick management of aggressive patients In 1800: most widely used sedative in asylums – In 1857: Bromide was the first agent to be introduced specifically as a sedative and soon thereafter as a hypnotic
  • 11. History • 1864: Barbiturates were introduced – Barbiturates were widely diverted from medical use and used on the street in the 60s where they were called “downers” and sold under a variety of different names. – Barbiturates had a low therapeutic index and were often used for suicide. Baeyer, discoverer of barbiturates Marilyn Monroe died of barbiturate overdose in 1962
  • 12. History • By 1990s, barbiturates replaced by benzodiazepines – 1961: introduction of chlordiazepoxide – Sternback is credited with the invention of chlordiazepoxide, diazepam, flurazepam, nitrazepam, clonazepam, and trimethaphan Leo Sternback
  • 13. History • Others and Z Drugs – Methaqualone (Quaalude) and meprobamate (Miltown) were used in the 60s as “non barbiturate tranquilizers”. • 1951: Methaqualone was synthesized in India as an antimalarial • 1965: the most commonly prescribed sedative in Britain • 1972: the sixth-bestselling sedative in the USA • discontinued in 1985, mainly due to its psychological addictiveness and recreational use – Z drugs: now replacing the BDZs; can be targeted to specific symptoms, insomnia and anxiety.
  • 14. SEDATIVE-HYPNOTIC DRUGS SEDATIVE-HYPNOTICS Benzodiazepines Barbiturates Miscellaneous agents Short Ultra Anxiolytics: action action Buspirone Intermediate Short Antidepressants action action Hypnotics: Long Long Z-drugs action action Antihistaminics Doxepin Ramelteon
  • 15. Barbiturates Long Acting Short Acting Ultra-short Acting • Phenobarbitone • Butobarbitone • Pentobarbitone • Thiopentone • Methohexitone o Epilepsy o Neonatal jaundice Anaesthesia
  • 16. Benzodiazepines a/c to Duration of Action Short acting • Triazolam • Oxazepam • Midazolam Intermediate acting Long acting • Alprazolam • Estazolam • Temazepam • Lorazepam • Nitrazepam • Diazepam • Flurazepam • Clonazepam • Chlordiazepoxide
  • 17. Benzodiazepines a/c to Indications Hypnotic Antianxiety Anticonvulsant • Diazepam • Flurazepam • Nitrazepam • Alprazolam • Temazepam • Triazolam • Diazepam • Chlordiazepoxide • Oxazepam • Lorazepam • Alprazolam • Diazepam • Lorazepam • Clonazepam • Clobazam
  • 18. Miscellaneous agents Z Drugs Melatonin receptor agonist Others • Zolpidem • Zopiclone • Zaleplon • Ramelteon • Antidepressants • Antihistaminics
  • 19. Site of Action • Midbrain ( RAS ) - Wakefulness • Limbic system - Thought & mental functions • Medulla - Muscle relaxation • Cerebellum - Ataxia  Effect : Limbic system > Midbrain RAS ⇓ - Therapeutic dose ⇒ Anxiolytic > Sedative - Higher dose ⇒ Depress RAS → Sedative & hypnotic effect
  • 21. Dose-response curves for two hypothetical sedative-hypnotics • Drug A: – An increase in dose higher than that needed for hypnosis may lead to a state of general anesthesia. – With higher doses, the drug will depress the respiratory and vasomotor centers which leads to coma. – Drug A is an example of alcohol and barbiturates. • Drug B: – needs greater doses to achieve CNS depression. – Drug B is an example of benzodiazepines and newer hypnotics.
  • 22. Dose-response curves for two hypothetical sedative-hypnotics • Drug A – Barbitutates – Steeper DRC – Narrow margin of safety • Drug B – Benzodiazepines – Flatter dose response curve – Greater margin of safety
  • 24. MOLECULAR PHARMACOLOGY OF THE GABA RECEPTOR • Pentameric transmembrane anion channel • composed of five subunits a, b, g and also d, e, p, r, etc. – there are six different a, four b, and three g • multiple BZD receptor subtypes • Two a1 and two b2 and one g2 subunits – most commonly expressed BZD receptor isoform
  • 25. MOLECULAR PHARMACOLOGY OF THE GABA RECEPTOR Ligand Subunit GABA b Barbiturate a or b Benzodiazepine a / g interface Z-drugs a1
  • 26. GABA-A RECEPTOR Cl CHANNEL BINDING SITE LIGANDS • Agonists – GABA: promotes Cl influx – Barbiturates: facilitates & mimics GABA action – Benzodiazepines: facilitate GABA action – Alcohol, Inhalational anaesthetics, propofol: open Cl channel directly • Antagonists – Bicuculline: competitive antagonist at GABA Rc – Flumazenil: competitive antagonist at BZD site – Picrotoxin: blocks Cl channel non-competitively • Inverse agonists – b-carbolines (DMCM – dimethoxyethyl-carbomethoxy-b- carboline): inverse agonist at BZD site – produce anxiety and seizures
  • 27. Barbiturates / Benzodiazepines Bind to GABAA receptor at different allosteric sites Facilitates GABA action Barbiturates increase duration & Benzodiazepines increase frequency of opening of Cl- channel Membrane hyperpolarization CNS depression At higher dose Barbiturates can act as GABA mimetic Mechanism of Action
  • 28. Mechanism of Action • Benzodiazepines  increase frequency of opening of Cl- channels induced by GABA (GABA facilitatory action)  increase binding of GABA to GABAA receptor • Barbiturates  increase duration of opening of Cl- channels induced by GABA (GABA facilitatory action)  at high conc.  can directly increase Cl- conductance through Cl- channels (GABA mimetic action)  inhibit Ca dependent release of neurotransmitters  depress glutamate induced neuronal depolarization through AMPA receptor  at very high conc. (anaesthetic doses)  depress voltage sensitive Na+ & K+ channels
  • 29. α γ α β GABA Bicuculline Diazepam Intra cellular side Flumazenil DMCM Barbiturate GABAA Receptor Barbiturate receptor BZD Receptor Cl-- Picrotoxin β
  • 31. Pharmacokinetics • well absorbed after oral administration 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 – Two-Phase Excretion Curve – 2 Half-Lives – Rapid drop in blood level as drug is redistributed; – Released from body fat;
  • 32. Pharmacokinetics • All barbiturates redistribute from the brain to the splanchnic areas, to skeletal muscle, and, finally, to adipose tissue.  CNS effects are 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)
  • 33. Actions • At low doses, produce sedation (have a calming effect and reduce excitement). • At higher doses, cause hypnosis, followed by anesthesia (loss of feeling or sensation), and, finally, coma and death. • Barbiturates do not raise the pain threshold and have no analgesic properties – may even exacerbate pain • Barbiturates suppress the hypoxic and chemoreceptor response to CO2, and overdosage is followed by respiratory depression and death. • Large dose cause circulatory collapse due to medullary vasomotor depression & direct vasodilatation.
  • 34. Therapeutic Uses: Barbiturates • Anesthesia: – The ultra–short-acting barbiturates, such as thiopental: used IV to induce anesthesia – but have largely been replaced by other agents. • Anticonvulsant: – Phenobarbital is used in long-term management of tonic–clonic seizures – can depress cognitive development in children and decrease cognitive performance in adults, and it should be used only if other therapies have failed. – Phenobarbital is used for the treatment of refractory status epilepticus
  • 35. Therapeutic Uses: Barbiturates • 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. • Hyperbilirubinemia and kernicterus in the neonates (increase glucouronyl transferase activity).
  • 36. Adverse effects • drowsiness, impaired concentration, and mental and physical sluggishness • The CNS depressant effects of barbiturates synergize with those of ethanol. • Hypnotic doses of barbiturates produce a drug “hangover” that may lead to impaired ability to function normally for many hours after waking.
  • 37. Adverse effects • 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
  • 38. Adverse Effects • Chronic use results in development of tolerance – Metabolic tolerance • Occurs with phenobarbital • Induces its own metabolism • 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
  • 40. Pharmacokinetics • lipophilic • rapidly and completely absorbed after oral administration • distribute throughout the body and penetrate into the CNS • Redistribution occurs from CNS to skeletal muscles& adipose tissue ( termination of action) • The longer-acting agents form active metabolites with long half-lives.
  • 41. Metabolism • All Benzodiazepines are metabolized in the liver – Phase I: ( liver microsomal system) – Phase II: glucouronide conjugation and excreted in the urine. • Many of Phase I metabolites are active: Increase elimination half life of the parent compound , cumulative effect with multiple doses. • EXCEPTION: No active metabolites are formed for (LEO) Lorazepam, Estazolam, Oxazepam. • Cross placental barrier during pregnancy and are excreted in milk (Fetal & neonatal depression)
  • 42. Actions • Reduction of anxiety – 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.
  • 43. Actions • Sedative/hypnotic – 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.
  • 44. Actions • 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.
  • 45. Actions • Anticonvulsant – Several benzodiazepines have anticonvulsant activity. – This effect is partially, although not completely, mediated by α1-GABAA receptors. • Muscle relaxant – 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.
  • 46. 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
  • 47. Adverse Effects • Drowsiness and confusion: Most common AE • Ataxia occurs at high doses • Cognitive impairment (decreased long-term recall and retention of new knowledge) can occur with use of benzodiazepines. • 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”
  • 49. 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, chlorazepate, diazepam & oxazepam
  • 50. Sleep disorders • decrease the latency to sleep onset and increase stage II of non–rapid eye movement (REM) sleep. • 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
  • 51. 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.
  • 52. Seizures • Clonazepam is used as an adjunctive therapy for certain types of seizures • lorazepam and diazepam are the drugs of choice in terminating status epilepticus. • Due to cross-tolerance, chlordiazepoxide, clorazepate, diazepam, lorazepam, and oxazepam are useful in the acute treatment of alcohol withdrawal and reduce the risk of withdrawal-related seizures.
  • 53. 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
  • 55. Benzodiazepines Barbiturates o Less neuronal depression o High therapeutic index o More neuronal depression o No anaesthesia even at high doses o Patient can be aroused o Loss of consciousness, o Low margin of safety o No effect on respiration or cardiovascular functions at hypnotic doses o Cause respiratory and cardiac depression o No effect on REM sleep o Less distortion of normal hypnogram o ++ suppression of REM sleep o Withdrawal ⇒ rebound ↑ in sleep o Hangover
  • 56. Benzodiazepines Barbiturates o Abuse liability very low o Tolerance o Dependence o No hyperalgesia o Hyperalgesia (↑ Sensitivity to pain) o Amnesia without automatism o Amnesia with automatism o Loss of short term memory o Not enzyme inducers – Less drug interactions o Potent enzyme inducers – More drug interactions o Specific antagonist – Flumazenil o No antagonist available
  • 57. Flumazenil: Benzodiazepine antagonist • FDA approval in 1991 • 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
  • 58. Other Anxiolytic Agents • Antidepressants – Selective serotonin reuptake inhibitors (SSRIs) such as escitalopram or paroxetine) or – serotonin/norepinephrine reuptake inhibitors (SNRIs), such as venlafaxine or duloxetine – SSRIs and SNRIs have a lower potential for physical dependence than the benzodiazepines and have become first-line treatment for GAD
  • 59. Other Anxiolytic Agents • Buspirone – Acts as a partial agonist at the 5-HT1A receptor presynaptically inhibiting serotonin release. • The metabolite 1-PP (1-(2-pyrimidyl-piperazine) has 2 receptor blocking action – Indicated for generalized anxiety disorders but takes 1 to 2 weeks to exert anxiolytic effects – no anticonvulsant or muscle relaxant properties – Advantages: • does not have sedative effects and does not potentiate CNS depressants • few side effects • relatively high margin of safety, • not associated with drug dependence • No rebound anxiety or signs of withdrawal when discontinued
  • 60. Other Anxiolytic Agents • Propranolol ( -blocker) – Use to treat some forms of anxiety, particularly when physical (autonomic) symptoms (sweating, tremor, tachycardia) are severe. • Clonidine ( 2-Adrenoreceptor Agonists) – used for the treatment of panic attacks – useful in suppressing anxiety during the management of withdrawal from nicotine and opioid analgesics
  • 61. Other Hypnotic Agents • Z-drugs: Zolpidem, Zaleplone, Zopiclone – not structurally related to benzo diazepines, 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.
  • 62. Other Hypnotic Agents • Ramelteon – 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)
  • 63. Other Hypnotic Agents • Antihistamines – Some antihistamines with sedating properties, such as diphenhydramine, hydroxyzine, and doxylamine, are effective in treating mild types of situational insomnia. – However, they have undesirable side effects (such as anticholinergic effects) that make them less useful than the benzodiazepines and the nonbenzodiazepines.
  • 64. Other Hypnotic Agents • Antidepressants – Doxepin an older tricyclic agent with SNRI mechanisms of antidepressant and anxiolytic action, was recently approved at low doses for the management of insomnia. – Other antidepressants, such as trazodone, mirtazapine and other older tricyclic antidepressants with strong antihistamine properties are used off-label for the treatment of insomnia
  • 65. Recent Advances • 5-HT2A receptor antagonists: – 5-Hydroxytryptamine (5-HT)2A antagonists are promising therapeutic agents for the treatment of sleep maintenance insomnias – unlike hypnotics, they have limited effects on sleep initiation. – 5-HT2A antagonists: eplivanserin, volinanserin • Orexin receptor antagonist – Orexin is believed to be responsible for maintaining wakefulness – Suvorexant, Elmorexant

Editor's Notes

  1. There is no clear cut demarcation for sedatives and hypnotics
  2. Porphyrias: a hereditary disorder of hemoglobin metabolism causing: -mental disturbance, -extreme sensitivity to light -and excretion of dark pigments in the urine
  3. Three BZDs undergo extrahepatic metabolism and do not form active metabolites: Oxazepam, Temazepam, Lorazepam (Out the Liver)
  4. Baclofen is a muscle relaxant that affects GABA receptors at the level of the spinal cord.
  5. Flunitrazepam: sedative-amnesic effects – “ date rape drug ”