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Sedative Hypnotics

Sedative-hypnotic drugs work by binding to GABA receptors in the brain and facilitating the action of the neurotransmitter GABA. This results in chloride ion influx, cell membrane hyperpolarization, and central nervous system depression. Sedatives primarily calm patients without inducing sleep, while hypnotics produce sleep resembling natural sleep. At higher doses, both sedatives and hypnotics can induce deeper stages of sedation including hypnosis, anesthesia, and coma. Common sedative-hypnotic drugs include benzodiazepines, barbiturates, antihistamines, antidepressants, and newer non-benzodiazepine drugs called Z-drugs. These drugs differ in their

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161 views3 pages

Sedative Hypnotics

Sedative-hypnotic drugs work by binding to GABA receptors in the brain and facilitating the action of the neurotransmitter GABA. This results in chloride ion influx, cell membrane hyperpolarization, and central nervous system depression. Sedatives primarily calm patients without inducing sleep, while hypnotics produce sleep resembling natural sleep. At higher doses, both sedatives and hypnotics can induce deeper stages of sedation including hypnosis, anesthesia, and coma. Common sedative-hypnotic drugs include benzodiazepines, barbiturates, antihistamines, antidepressants, and newer non-benzodiazepine drugs called Z-drugs. These drugs differ in their

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Hemant
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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%

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 • 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

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