Sedative – Hypnotic Drugs

Anxiolytic Drugs Minor Tranquilizers

Sedative – Hypnotic Drugs

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

Basic Features

Overlapping actions. General CNS depressants. Abuse potential. Additive effects.

Dose-response curves for two hypothetical sedative-

hypnotics.

Ideal Anxiolytic

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

Children's Anxiety Scale

PANIC, Panic disorder and agoraphobia; FEARS, Fears of physical injuryGAD, generalized anxiety disorder.SAD, separation anxiety disorderSOCPH, social phobiaOCD, obsessive–compulsive disorder.

Ideal Hypnotic

Patient should go asleep quickly. Maintains sleep of sufficient

quality and duration. Patient awakes refreshed

without “hangover”( التى ا البغيضة آلثار.( تخلف

Benzodiazepines

200 synthesized(1960s-2000). Receptor is associated with GABA

receptor. Increase affinity of GABA for GABA I

receptors. Increase the frequency of Cl- channel

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

GABAA Receptor

Chloride ion channel. Pentameric structure assembled

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

Subunits of these classes are characterized.

GABAA Receptor

Binding sites of GABA are located between adjacent α1and β2 subunits.

Binding site for benzodiazepines is between α1and α2 subunits.

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

BZs bind to many of these. Zolpidem binds only to isoforms

containing α1 subunits

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

Chemical structures of some benzodiazepines

Biotransformation of benzodiazepines

Benzodiazepines

Cause dose-dependant CNS depression.

Wide margin of safety. Relatively mildly addictive.

Adverse Effects of Benzodiazepines

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

Withdrawal Symptoms of Benzodizepines Rebound Insomnia and Anxiety. Tremor, N.V., Weight loss,

Convulsions.

Barbiturates Old fashioned(1930-1960s) sedative-

hypnotic drugs. Also facilitate the actions of GABAA

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

At high concentrations might work directly.

Might also depress excitatory neurotransmitters like glutamic acid.

Barbiturates Hangover Effects Deaths were(1960s) common, “Drug

Automatism“ Abuse , Tolerance , Dependence and

Withdrawal. Interactions are common, can induce

liver enzymes.

Barbiturates

Thiopental Amobarbital Pentobarbital Phenobarbital Differ in durations of action and

consequently in their uses.

Chemical structures of some barbiturates and other sedative-hypnotics.

Buspirone Anxiolytic, needs a week to work. No sedative, anticonvulsant or muscle

relaxant effects. 5HTA1A partial agonist. Works also on D2

receptors . Safe: Tachycardia, GIT distress, paresthesia

and pupillary constriction. No dependence or tolerance. No rebound or withdrawal. No additive effects to others. Minimal abuse liability.

Zolpidem

Good sedative. Wide spectrum but weak. Binds to benzodiazepine

receptor. Short acting. Preserves normal sleep. GI side effects (diarrhea).

Ramelteon Melatonin receptor agonist (MT1 and

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

rhythm. Effects on sleep and endocrine

system. Might be useful for “jet lag”.

Chemical structures of newer hypnotics

Antihistamines

Hydroxyzine Diphenhydramine. Promethazine. These are non addictive, uncontrolled

drugs( over the counter), and have anticholinergic side effects.

- adrenergic Blockers

Best drugs for Performance Anxiety (Stage Fright).

Will inhibit the symptoms of sympathetic activity associated with anxiety(nervousness, palpitations, sweating, tremor, coldness)

Will not affect the level of consciousness.

Antidepressants

General anxiety. Phobic( الرهاب) and Panicالرعب) (Disorders. Obsessive-compulsive states.

Paraldehyde. Meprobamate:

Muscle Relaxant , 1951 Geriatric patients.