Sedative – Hypnotic DrugsAnxiolytic DrugsMinor Tranquilizers

Munir Gharaibeh, MD, PhD, MHPESchool of Medicine,

The University of JordanMarch, 2018

Sedative – Hypnotic Drugs

Spectrum of Activity:n Decreased Anxiety. n Sedation.n Sleep(Hypnosis).n Death.

March 18 2Munir Gharaibeh MD, PhD, MHPE

Dose-response curves for two hypothetical sedative-

hypnotics.

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Sedative – Hypnotic Drugs

Common Basic Features:n Have overlapping actions.n General CNS depressants. n Have abuse potential. n Have additive effects.

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Ideal Anxiolytic

n Calm the patient without too much day time sedation and drowsiness and without producing dependence.

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Ideal Hypnotic

n Patient should go asleep quickly.n Maintains sleep of sufficient

quality and duration.n Patient awakes refreshed

without “hangover” ( تافلخم ).

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Sleep Cycles n In normal persons, sleep is

divided into two cycles.n Each sleep cycle lasts for about

90 to 120 minutes.n A night has four to six different

sleep cycles.n Disturbance of these cycles by

physical, mental factors, or drugs, results in sleep problems.

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Non-REM (NREM) Sleep n Has 3 stages 1,2,3 n Stage 3 is also known as Slow Wave

Sleep or Deep Sleep.n Predominates in the first half of the

night.n Deep sleep has been associated with

body and brain restitution (e.g. daytime function or feeling rested or energetic upon awaking).

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REM Sleep n Rapid eye movement (REM) sleepn More frequent in the second half of

the night.n Associated with promotion of

emotional and/or mental functions, including memory.

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Benzodiazepinesn 200 synthesized. n Receptor is associated with GABA

receptor. n Increase affinity of GABA for GABA I

receptors.n Increase the frequency of Cl- channel

opening events leading to hyperpolarization and postsynaptic inhibition and decreased transmission.

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GABAA Receptor

n Chloride ion channel.n Pentameric structure

assembled from 5 subunits( each with 4 transmembrane-spanning subunits) selected from multiple polypeptide classes(α, β …etc).

March 18 12Munir Gharaibeh MD, PhD, MHPE

GABAA Receptorn Binding sites of GABA are located

between adjacent α1and β2subunits.

n Binding site for benzodiazepines lies between α1and α2 subunits.

n GABA receptors in different areas of the CNS consist of various combinations of the essential subunits.

n Benzodiazepines bind to many of these.

n Zolpidem binds only to isoforms containing α1 subunits March 18 13Munir Gharaibeh MD, PhD, MHPE

A model of the GABAA receptor-chloride ion channel macromolecular complex

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Benzodiazepines(1960s)

n Weak bases, absorbed in intestine

n Redistributed n Metabolized. n Weak inducers of liver enzymes.

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Chemical structures of some benzodiazepines

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Biotransformation of Benzodiazepines

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Benzodiazepines

n Cause dose dependant CNS depression.

n Have wide margin of safety.n Have few side effects.

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Adverse Effects of Benzodiazepines

n CNS depression ----- Tolerance.n Blurring of vision.n Hallucinations.n Paradoxical Reactions----- Excitementn GI , Blood ------ Rare.n Additive. n Overdose: Flumazenil.

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Withdrawal of Benzodizepinesn Rebound Insomnia and Anxiety. n Tremor, N.V., Weight loss,

Convulsions.

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Barbiturates(1935)n Also facilitate the actions of GABAA at

multiple sites but appear to increase the duration of GABAA gated Cl- channel opening.

n Might also depress excitatory neurotransmitters like glutamic acid.

n Hangover Effects.n Liver enzyme inducers.n Deaths(1950s-1960s): Drug Automatism n Abuse , Tolerance , Dependence and

Withdrawal. n Interactions.

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Barbiturates

n Thiopental (ultra short acting).n Amobarbital(short acting)n Pentobarbital( intermediate

acting).n Phenobarbital( long acting).

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Buspironen Anxiolytic, needs a week to work.n No sedative, anticonvulsant or

muscle relaxant effects.n 5HTA1A partial agonist. Works also

on D2 receptors .n Safe: Tachycardia, GIT distress,

paresthesia and pupillary constriction.• No dependence or tolerance. • No rebound or withdrawal.• No additive effects to others.• Minimal abuse liability.March 18 24Munir Gharaibeh MD, PhD, MHPE

Zolpidemn Good sedative.n Wide spectrum but weak. n Binds to benzodiazepine

receptor.n Short acting.n Preserves normal sleep.n GI side effects (diarrhea).n CNS : additive.

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Ramelteonn Melatonin receptor agonist (MT1 and

MT2).n Not a controlled substance.n Melatonin is involved in circadian

rhythm.n Have effects on sleep and endocrine

system.n Might be useful for jet lag.

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Antihistamines

n Hydroxyzinen Diphenhydramine.n Promethazine.

• Antihistamines which have sedative side effects.

• Non prescription drugs.• Have anticholinergic side effects (

dryness, urinary retention ….).• No problems of tolerance and

dependanceMarch 18 27Munir Gharaibeh MD, PhD, MHPE

b - adrenergic Blockers

n Reduce the sympathetic manifestations of anxiety ( tremor, nervousness, tachycardia, sweating…..).

n The most useful in performance anxiety (Stage Fright Anxiety or Phobia), because they do not depress the CNS.

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Antidepressants

n General anxiety.n Phobic and Panic Disorders.n Obsessive-compulsive states.

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Chloral Hydrate

n 1800s. n Effective.n Metabolized into TCE.n Causes bad smell and taste ,

gastric irritation , allergy , and arrhythmia.

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Others

n Paraldehyde.

n Meprobamate:Muscle Relaxant , 1951 good for geriatric patients.

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