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 injury GAD, generalized anxiety disorder. SAD, separation anxiety disorder SOCPH, social phobia OCD, obsessive–compulsive disorder.

Ideal Hypnotic Patient should go asleep quickly. Maintains sleep of sufficient quality and duration. Patient awakes refreshed without “hangover”(الآثار البغيضة التى 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.

Chloral Hydrate 1800. Effective. TCE. Sharp smell and taste , gastric irritation , allergy , arrhythmia.

Paraldehyde. Meprobamate: Muscle Relaxant , 1951 Geriatric patients.