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

Barbiturates

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u Superseded by more selective drugs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

Benzodiazepines

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