CNS Depressants

Includes alcohol & a wide variety of drugs used as sedatives, sleeping pills, anti-anxiety tranquilizers, anesthetics, and anti-convulsants.

Dose-Dependent CNS Depression

u   Depending on dose, you may experience

l  calming, relief from stress/anxiety

l  disinhibition, intoxication

l  sedation

l  sleep

l  anesthesia

l  coma

l  death

 General CNS Depressants

u   Dose-dependent CNS depression

u   Additive or, more often, synergistic interaction with other depressants

u   Cross-tolerance and cross-dependence

u   Hyperexcitability rebound afterwards

u   Low doses may appear “stimulating” because of depression of inhibitions

u   Withdrawal can be dangerous


Classic non-selective CNS sedative/hypnotics or “downers” that dominated the market 1903-1960

Barbiturate History

u   Developed in the 1860’s by Adolph Bayer

u   1st marketed in 1903; over 50 developed

u   Leading depressant group for ~50 years

u   Only ~12 varieties currently used

u   Superseded by more selective drugs

Characteristics of Barbiturates

u   Barbs differ in length of action (ultrashort (mins.), short <4 hr, intermediate 4-6 hr , long >6 hr) Affect brainstem reticular formation

u   General depressant effects almost indistinguishable from those of alcohol

u   Depressant action due to increasing the inhibitory effects of GABA and triggering inhibition even in the absence of GABA

u   Higher doses affect other transmitters.

GABA Receptor

Some Well-Known Barbs

u   sodium thiopental (Pentothal)(U)

u   secobarbital (Seconal)(S)

u   pentobarbital (Nembutal)(S)

u   amobarbital (Amytal)(I)

u   phenobarbital (Luminal)(L)

u   These drugs were widely used as sedative/hypnotics, anesthetics, anticonvulsants

Problems With Barbs

u    Nonselective effect even at low doses

u    Low safety margin; easy to overdose & cause lethal depression of breathing; used in suicides

u    Dangerous interaction with other depressants

u    Rapid development of tolerance

u    Risk of significant dependence

u    Possible life-threatening withdrawal

u    Decreased REM; morning grogginess

u    Withdrawal rebound in insomnia & anxiety

u    Memory  and cognition impaired (like alcohol)

u    2-3 X increase in birth defects

Barbiturate Withdrawal

u   begins with growing anxiety, agitation, the shakes, GI upset & bodily arousal

u   severe withdrawal includes delirium, seizures, uncontrolled HR & possible death, even with medical supervision

u   This dose-dependent withdrawal, is very similar to alcohol withdrawal & is characterized by hyper-excitability of body and brain.


Barb Use in H.S.

Reasonable Use of Barbs

u    To control seizures (only good use of oral barbs)

u    As an intravenous anesthetic

u    Sedation in emergencies or in therapy

u    To reduce brain activity, blood flow & release of glutamate after severe head injury

u    In assisted suicides

u    Barbs should not be used as anxiolytics or hypnotics

“Non-Barbiturate” Sedative-Hypnotics


u   Examples:

l  methaqualone (Quaalude)

l  meprobamate (Miltown)

u   Promoted as an improvement but turned out not to be


u   “Minor Tranquilizers” or “Anxiolytics”

u   More selective CNS Depressants (doses that relieve anxiety do not produce as much general depression as barbs)

u   15 different benzos currently available

u   Benzodiazepine binding site on GABA receptor

Long Acting Benzodiazepines

u    *Valium - diazepam

u    *Librium - chlordiazepoxide

u    Dalmane – flurazepam

u    Paxipam - halazepam

u    Centrax - prazepam

u    Tranxene - chlorazepate          

u    Provide sustained effects when needed (anticonvulsant; muscle relaxant; alcohol withdrawal; for those with both insomnia & daytime anxiety)

u    Avoided in the elderly

Short and Intermediate Acting Benzodiazepines


u    *Xanax  - alprazolam

u    Halcion - triazolam

u    Versed (midazolam)

u    Serax – oxazepam

u    Ativan - lorazepam

u    Klonopin - clonazepam

u    Restoril - temazepam

u    Pro-Som - estazolam


Treatment of Anxiety Disorders

u    Panic Disorder – Xanax & Klonopin are FDA approved, others used “off-label”

u    Effective within 1-2 weeks; results in up to 75% being free of attacks

u    No tolerance to therapeutic effect

u    Recurrent panic attacks upon withdrawal (25-50%) so long gradual over several months recommended

u    Side effects: sedation/drowsiness (38-75%);

   memory impairment in up to 15%


Generalized Anxiety Disorder

u   All benzos equally effective – produce moderate-marked improvement in 66%

u   Effective in 1-2 weeks; ~ 50% smaller dose needed than panic disorder; no tolerance to this effect over years

u   Especially good for somatic symptoms


Social Anxiety Disorder

u   Xanax & Klonopin demonstrated to be effective in ~ 78%

u   BUT: this patient group often has comorbid  alcohol/substance abuse which complicates the use of bezos

*Rohypnol - the “date-rape drug”

u   “Roofies” are a potent benzodiazepine (flunitrazepam)  not marketed in the US but similar to Halcion. Actually any combination of alcohol + sufficient benzo could produce similar effects.

Benzodiazepine Benefits

u   more selective anti-anxiety action, lower levels of depressant side effects

u   wide safety margin (high LD) as long as other depressants aren’t used

u   antagonist *flumazenil  (Romazicon) available for overdose situations

u   less tolerance and dependence

u   less dangerous withdrawal

u   sleep is more normal than with other depressants

Problems With Benzodiazepines

u    dependency still possible

u    may be rebound insomnia &anxiety when stopped

u    over-response in elderly common; idiosyncratic responses possible

u    may impair memory

u    may cause birth defects

u    driving problems common

u    don’t solve original problem in most cases; may be overprescribed

The Search for
Even More Selective Drugs

u   more “selective”drugs affect only a sub-group of receptors

u   Selective 5HT-1A agonist buspirone  (Buspar) (not a CNS depressant)

l  Antianxiety action (delayed) without other depressant effects

u   Selective GABA-A1 agonists zolpidem (Ambien) & zaleplon (Sonata)

l  Hypnotic effects without antianxiety, anticonvulsant or muscle relaxing effects

Alternatives to Depressants

u   Antihistamines

l  diphenhydramine (Benedryl)

l  hydroxyzine (Atarax, Visteril)

l  promethazine (Phenergan)

u   Beta-blockers

l  propranolol (Inderal)

u   Antidepressants

l  amitriptyline (Elavil) & doxepin (Sinequan)  used for sleep

l  SSRIS now used for most anxiety disorders