Sedative

Hypnotics
AMRUTH KIRAN

LECTURER

CABIN NO. 217

D E PA R T M E N T O F P H A R M A C O L O G Y

D B M S , M A H E , M A N I PA L
OBJECTIVES
✓Classify drugs with examples

✓Explain the pharmacological effects, uses and side effects of

benzodiazepines and barbiturates

✓Explain conscious sedation

Counting
Sheep
Sedatives – Hypnotics
Sedative Hypnotic

A drug that reduces excitement, calms the A drug which produces sleep resembling
patient without inducing sleep natural sleep

Sedatives in therapeutic dose act like anxiolytic Used for initiation and / or maintenance of
agent sleep

In larger doses produce hypnosis (trans like

state in which subject becomes passive and In higher doses produce general anesthesia
highly suggestible)

Site of action is on the limbic system which Site of action is on the midbrain and ascending
regulates thought and mental function RAS which maintain wakefulness
Anxiolytics
•Anxiety is an unpleasant state of tension, apprehension, or uneasiness
that arises from either a known or 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 hyperactivity.
History
•Alcohol and potions containing
laudanum/morphine, herbs which induce
sleep

•Morphine in the 1800s

•1857 – bromide – 1st agent as sedative and

hypnotic
History
•In 1990s, barbiturates replaced by
Benzodiazepines
• 1961 – Introduction of chlordiazepoxide

• Sternback is credited with the invention

of chlordiazepoxide, diazepam,
flurazepam, nitrazepam, clonazepam and
trimethaphan
Classification
A. Benzodiazepines (BZD):
✓ Short acting: midazolam

✓ Intermediate acting: alprazolam, lorazepam

✓ Long acting: diazepam, clonazepam

Classification
B. Non-benzodiazepines: zolpidem, zaleplon

C. Barbiturates: phenobarbital, pentobarbital

D. Melatonin analogues: ramelteon

Neurotransmitters
✓Excitatory: Acetylcholine, glutamate, epinephrine, norepinephrine,
dopamine and histamine

✓Inhibitory: GABA (γ-Aminobutyric acid), glycine and serotonin

Barbiturates
✓Formerly the mainstay of treatment to sedate patients or to induce
and maintain sleep

✓Present day largely replaced by the BZDs (tolerance and physical

dependence)

✓All barbiturates are controlled substances

GABA binding site

GABA A receptor:
 Barbiturates bind to GABA : BZD receptor – Cl¯ channel complex

Increases the lifetime of Cl¯ channel opening induced by GABA

Potentiate GABAergic inhibition

Membrane hyperpolarization and reduction in membrane excitability

CNS depression
MOA
✓Enhance BZD binding to its receptor

✓At high concentrations, directly increase Cl¯ conductance (GABA-mimetic

action) and inhibit Ca2+ dependent release of neurotransmitters

✓Depress glutamate induced neuronal depolarization through AMPA receptors

✓At very high concentrations, depress voltage sensitive Na+ and K+ channels as
well.
Pharmacological Actions of
Barbiturates
CNS Actions:

✓Dose dependent action: Sedation (Sedative) → Sleep (Hypnotic) →

Anaesthesia (Anesthetic) → Coma → Death

✓Impair learning, short-term memory and judgement

✓No analgesic action; small doses may even cause hyperalgesia

✓Euphoria may be experienced by addicts

Pharmacological Actions of
Barbiturates
CNS Actions:

✓Depress all areas of the CNS, but reticular activating system (RAS) is the
most sensitive; its depression is primarily responsible for inability to
maintain wakefulness
Pharmacological Actions of
Barbiturates
Sedative-Hypnotic:

✓Shortens the time taken to fall asleep and increases sleep duration

✓Sleep is arousable, but the subject may feel confused and unsteady if
waken early

✓Night awakenings are reduced

Pharmacological Actions of
Barbiturates
Sedative-Hypnotic:

✓REM and stage 3, 4 sleep are decreased; REM–NREM sleep cycle

is disrupted

✓Less effect if the drug is consumed daily

✓A rebound increase in REM sleep and nightmares if the drug is

discontinued after few nights use
Pharmacological Actions of
Barbiturates
Sedative-Hypnotic:

✓Hangover (dizziness, distortions of mood, irritability and lethargy)

may occur in the morning after a nightly dose

✓If given at daytime can produce drowsiness, reduction in anxiety

and excitability

✓No selective antianxiety action

Pharmacological Actions of
Barbiturates
Anticonvulsant:

✓Phenobarbital and metharbital (converted to phenobarbital in the

body) are effective in the treatment of generalized tonic-clonic
seizures, though not the drugs of first choice

✓Anticonvulsant action is independent of general CNS depression.

Pharmacological Actions of
Barbiturates
Respiration:

✓Suppress the hypoxic and chemoreceptor response to CO2

✓Overdosage is followed by respiratory depression and death.

Pharmacological Actions of
Barbiturates
CVS:

✓Hypnotic doses produce a slight ↓ in BP and heart rate.

✓Toxic doses produce marked fall in BP due to vasomotor centre

depression, ganglionic blockade and direct ↓ in cardiac contractility.

✓Reflex tachycardia can occur, though pressor reflexes are depressed.

Pharmacological Actions of
Barbiturates
Skeletal & Smooth Muscles:

✓Anaesthetic doses reduce skeletal muscle contraction by action on

neuromuscular junction.

✓Tone and motility of bowel is decreased slightly by hypnotic doses;

more profoundly during intoxication
Pharmacological Actions of
Barbiturates
Kidney:

✓Reduce urine flow by ↓ BP and increasing ADH release

✓Oliguria (less quantity of urine) attends barbiturate intoxication

Therapeutic Uses of Barbiturates
✓Epilepsy (phenobarbitone)

✓Anaesthesia (thiopentone)
Adverse effects of Barbiturates
✓Side effects: Hangover, mental confusion, impaired performance

✓Idiosyncrasy: excitement (elderly), precipitation of porphyria

✓Hypersensitivity: Rashes, swelling of eyelids, lips, etc…

✓Tolerance and dependence: development of cellular and

pharmacokinetic tolerance, psychological as well as physical dependence
on repeated use.
Adverse effects of Barbiturates
✓Withdrawal symptoms: excitement, hallucinations, delirium, convulsions and death

Acute barbiturate poisoning: accidental or abuse

✓2–3 g for the more lipid-soluble agents (short-acting barbiturates) and 5–10 g for less

lipid-soluble phenobarbitone

✓Signs & symptoms: patient is flabby and comatose with shallow and failing

respiration, fall in BP and cardiovascular collapse, renal shut down, pulmonary

complications, bullous eruptions

Adverse effects of Barbiturates
Treatment of Acute barbiturate poisoning:

✓Gastric lavage: leave a suspension of activated charcoal in the stomach

to prevent absorption of the drug from intestines.

✓Supportive measures: such as, patent airway, assisted respiration,

oxygen, maintenance of blood volume by fluid infusion and use of

vasopressors—dopamine may be preferred for its renal vasodilating action.

Adverse effects of Barbiturates
Treatment of Acute barbiturate poisoning:

✓Alkaline diuresis: with sodium bicarbonate 1 mEq/kg i.v. with or without

mannitol is helpful only in the case of long-acting barbiturates which are
eliminated primarily by renal excretion.

✓Haemodialysis and haemo-perfusion (through a column of activated charcoal

or other adsorbents) is highly effective in removing long-acting as well as short-
acting barbiturates.
BZDs
✓Promote the binding of the major inhibitory neurotransmitter γ-
aminobutyric acid (GABA) to the GABAA subtype of GABA
receptors, (multi-subunit, ligand gated chloride channels) →
enhancing the GABA-induced ionic currents through these channels

✓Sedative-hypnotic, muscle-relaxant, anxiolytic, and anticonvulsant

effects
Based on duration of action (BZD)
✓Short acting: midazolam, triazolam, oxazepam

✓Intermediate acting: alprazolam, lorazepam, nitrazepam,

estazolam, temazepam

✓Long acting: diazepam, clonazepam, chlordiazepoxide, flurazepam

Site of Action
✓Midbrain: Wakefulness

✓Limbic System: Thought and Mental

Functions

✓Medulla: Muscle Relaxation

✓Cerebellum: co-ordination, balance and

speech
Site of Action
✓Effect: Limbic System > Midbrain

✓Therapeutic Doses: Anxiolytic > Sedative

✓Higher Doses: Depresses Midbrain → Sedative and Hypnotic Effect

GABA binding site

GABA A receptor:
 BZDs bind between α and γ subunits of GABAA receptor

Facilitate GABA binding to GABAA receptor

Increase the frequency of Cl- channel opening

Membrane hyperpolarization and reduction in membrane excitability

CNS depression: sedation and relief of anxiety, amnesia, hypnosis, anesthesia,

coma and respiratory depression (Dose dependent)
MOA
Pharmacological Actions of BZDs
CNS Actions:

✓Not generally depressants → exert relatively selective anxiolytic,

hypnotic, muscle relaxant and anticonvulsant effects

✓i.v. anaesthetic dose → some degree of awareness is maintained

(anterograde amnesia – mediated by the α1-GABAA receptors)

✓Ability to learn and form new memories is also impaired

Pharmacological Actions of BZDs
Antianxiety action:

✓Relatively selective antianxiety action

✓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.

✓Chronic administration → drowsiness wanes off due to development of

tolerance
Pharmacological Actions of BZDs
Sedative-Hypnotic:

✓Hasten onset of sleep, reduce intermittent awakening and increase

total sleep time (specially in those who have a short sleep span)

✓The hypnotic effects are mediated by the α1-GABAA receptors

✓Shorten REM phase, but more REM cycles may occur, so that effect
on total REM sleep is less marked
Pharmacological Actions of BZDs
Sedative-Hypnotic:

✓The latency of sleep onset is decreased (time to fall asleep)

✓The duration of stage 2 NREM (non-rapid eye movement) sleep is

increased

✓The duration of REM (rapid eye movement) sleep is decreased

✓The duration of stage 4 NREM slow-wave sleep is decreased.

Pharmacological Actions of BZDs
Sedative-Hypnotic:

✓Night terrors and body movements during sleep are reduced

✓Most subjects wake up with a feeling of refreshing sleep.

✓Development of tolerance towards sleep promoting action of BZDs

after repeated nightly use.
Pharmacological Actions of BZDs
Muscle relaxant:

✓Centrally mediated skeletal muscle relaxation without impairing

voluntary activity

✓High doses relax the spasticity of skeletal muscle, by increasing

presynaptic inhibition in the spinal cord, via α2-GABAA receptors
(depress neuromuscular transmission)
Pharmacological Actions of BZDs
Anticonvulsant:

✓Effective for short-term use in status-epilepticus mediated by α1-

GABAA receptors without marked CNS depression (psychomotor
function may be impaired)

✓Chronic use – development of tolerance to the anticonvulsant action

✓i.v. diazepam (but not others) causes analgesia

Pharmacological Actions of BZDs
Respiration:

✓Hypnotic doses of benzodiazepines → no effect on respiration in normal

subjects

✓Special care must be taken in the treatment of children and individuals with
impaired hepatic function (alcoholics)

✓Higher doses slightly depress alveolar ventilation and cause respiratory acidosis
especially in COPD patients
Pharmacological Actions of BZDs
CVS:

✓CVS effects are minor except in severe intoxication

✓Preanesthetic doses, all BZDs ↓ blood pressure and ↑ heart rate

✓i.v. diazepam can produce short-lasting coronary dilatation

✓Large doses, midazolam ↓ cerebral blood flow and oxygen

assimilation considerably
Pharmacological Actions of BZDs
Others:

✓Diazepam decreases nocturnal gastric secretion and prevents stress

ulcers.
Therapeutic Uses of BZDs
✓ Anxiety neuroses

✓ Treat insomnia
✓Transient insomnia – lasts < 1 week, jet lag, shift work

✓Short term insomnia – lasts for 1 – 3 weeks, pain, surgery

✓Long term insomnia – lasts > 3 weeks, underlying disease

Therapeutic Uses of BZDs
✓Transient insomnia – short acting BZDs

✓Short-term insomnia – intermediate acting BZDs

✓Long-term insomnia – long-acting BZDs

Therapeutic Uses of BZDs
✓As anxiolytic and for day-time sedation

✓As anticonvulsant, especially emergency control of status

epilepticus, febrile convulsions, tetanus, etc

✓As centrally acting muscle relaxant

✓Preanesthetic medication, i.v. anaesthesia and conscious sedation

Therapeutic Uses of BZDs
✓Treat convulsions skeletal muscle spasm associated with spinal injuries,
tetanus, cerebral palsy and those receiving ECT

✓Minor procedures

✓Alcohol withdrawal symptoms

✓Along with analgesics, NSAIDs, spasmolytics, antiulcer and as adjuvants

to treat nonspecific dyspeptic symptoms
Therapeutic Uses of BZDs According
to Indications
✓Hypnotic: Diazepam, flurazepam, nitrazepam, alprazolam,
temazepam, triazolam

✓Antianxiety: Diazepam, chlordiazepoxide, oxazepam, lorazepam,

alprazolam

✓Anticonvulsant: Diazepam, lorazepam, clonazepam, clobazam

Adverse effects of BZDS
✓Dose-dependent drowsiness, fatigue, disorientation, lethargy, vertigo, ataxia,
disorientation, amnesia, prolonged reaction time, impairment of psychomotor skills,
hangover, Weakness, blurring of vision, dry mouth and urinary incontinence

✓Tolerance to their sedative effects develops slowly

✓Cross tolerance to alcohol and other CNS depressants

✓Dependence due to down-regulation of GABA receptor

Adverse effects of BZDS
✓BZD withdrawal – anxiety, insomnia, tremors, palpitation, impaired

concentration

✓Floppy baby syndrome if used during labor – hypotonia (flaccidity)

and respiratory depression in the newborn

✓Flurazepam – paradoxical stimulation, irritability and sweating

CAUTION
✓Should be used cautiously in patients with liver disease

✓Should be avoided in patients with acute angle-closure glaucoma

✓Alcohol and other CNS depressants enhance the sedative–hypnotic

effects
BZD Antagonist
✓In case of BZD OD – Flumazenil i.v. (GABA receptor
antagonist)

✓Administration of flumazenil may precipitate withdrawal in

dependent patients or cause seizures if a benzodiazepine is used
to control seizure activity

✓Dizziness, nausea, vomiting, and agitation are the most

common side effects
BZDs & Barbiturates
BZDs Barbiturates
Less neuronal depression More
High therapeutic index Low
No anesthesia even at high doses Loss of consciousness
Patients can be aroused Low margin of safety
No effect on respiration, cardiovascular Cause respiratory and cardiac
function at hypnotic doses depression
More suppression of REM sleep
No effect on REM sleep Withdrawal → rebound increase in
Less distortion of normal hypnogram sleep
Hangover
BZDs & Barbiturates
BZDs Barbiturates

Low abuse liability Tolerance, dependence

No hyperalgesia (sensitivity to pain) Hyperalgesia

Amnesia with automatism

Amnesia without automatism
Loss of short-term memory
No enzyme induction – less drug
Potent enzyme inducer
interactions
Antagonist (flumazenil) No antagonist
Conscious Sedation
✓Is a monitored state of altered consciousness that can be employed

(supplemented with local/regional anaesthesia), to carryout

diagnostic/short therapeutic/dental procedures in apprehensive

subjects or medically compromised patients, in place of general

anaesthesia
Conscious Sedation
✓Allows the operative procedure to be performed with minimal

physiologic and psychologic stress

✓CNS depression produced by the drugs used can withstand trespass of the

procedure, while maintaining communication with the patient, who at the

same time responds to commands and is able to maintain a patent airway.

Conscious Sedation
✓The difference between conscious sedation and anaesthesia is one of

degree

✓The protective airway and other reflexes are not lost, making it safer

✓Drugs used: Diazepam (1 – 2 mg), midazolam, propofol, nitrous

oxide with 100% O2, fentanyl (1–2 mcg/kg every 15–30 min)