CNS effects of sedative hypnotics

Barbiturates: cause dose dependent depression that extends from sedation to anesthesia to respiratory depression and death (EtOH works the same)

Benzodiazepines: reach a plateau in CNS depression and are therefore SAFER!!! 

MOA of sedative hypnotics

works on one of 5 subunits of the GABAa receptor and w/ activation allows the influx of Cl-, causing hyperpolarization

Benzo's: bind to the gamma subunit and increase the FREQUENCY of Cl- channel opening

BZ1 = mediates sedation

BZ2 = mediates antianxiety, impaires cognition

Barb's: bind to the beta subunit and increase the DURATION of Cl- channel opening

Flumazenil

Benzodiazepine receptor antagonist that is used as an antidote to reverse the CNS depression caused by overdose.

CAN NOT reverse effects of barbiturates and alcohols

Benzo's and thier indications

alprazolam: anxiety, panic, phobias

diazepam: anxiety, preop sedation, muscle relaxation, w/drawl states

lorazepam: anxiety, preop sedation, status epilepticus

midazolam: preop sedation, anesthesia

temazepam: sleep disorders

oxazepam: sleep disorders, anxiety

OTL (oxazepam, temazepam, lorazepam) conjugated outside the liver

Half life: midazolam < oxazepam < temazepam < alprazolam < lorazepam < diazepam

Withdrawl signs: rebound insomnia, anxiety, seizures

Barbiturates and their indications

Phenobarbital: used for seizures

Thiopental: induction of anesthesia

General inducers of CYP450

Contraindication in porphyrias (increases heme synthesis)

Withdrawl signs of barbs and ethanol: anxiety, agitation, life-threatening seizures (delirium tremens) manage w/ long acting BZ's

Zolpidem (non BZ drug)

BZ receptor agonist, less effect on cognitive function

Overdose reversed by flumazenil

Used in sleep disorders (trade name ambien)

Buspirone

5HT1A partial agonist (no effect on GABA)

Used for generalized anxiety disorders

NON-sedative

Take 1-2 weeks for effects but has low abuse liability and is not additive w/ other CNS depressants

Alcohols (MOA - general) 

All cause CNS depression through GABA mimetic activity

All cause metabolic acidosis

Ethylene glycol

Ethylene Glycol --> glycoaldehyde --> glycolic acic

EtOH dehydrogenase  Aldehyde dehydrogenase

(catalytic enzymes for the above rxn)

SE: Nephrotoxicity

Methanol

Methanol --> Formaldehyde --> Formic Acid

EtOH dehydrogenase   Aldehyde dehydrogenase

(Catalytic enzymes for the above rxn)

SE: respiratory failure, Ocular damage (snow storm, blurred vision)

Treatment for overdose of ethylene glycol, or methanol

Fomepizole (long acting inhibitor of alchol dehydrogenase)

Ethanol

Ethanol --> Acetaldehyde --> Acetic acid

EtOH dehydrogenase      Acetaldehyde dehydrogenase

SE: acetaldehyde toxicity (N/V, HA, hypotension, combines w/ folate to inactivate it, combines w/ thiamine to decrease availability

Disulfiram

 Inhibits Acetaldehyde dehydrogenase causing a build up of acetaldehyde

Drugs that cause a disulfiram like rxn:

-Metronidazole

-Cefamandole, Cefoperazone, Cefotetan

-Chlorpropamide

Chronic Alcoholism (effects on body) 

1. hypoglycemia

2. fatty liver and lipemia

3. muscle wasting

4. gout (lactate competes w/ urate for excretion)