CNS Depressants

Question 1

Prototype Drugs

Answer 1

Benzos:
Diazepam (Valium)
Triazolam (Halcion)
Non-Benzos, Benzo Agonists (NBRAs):
Zolpidem (Ambien)
Eszopiclone (Lunesta)
Alcohols:
Ethanol (whiskey) 
Methanol (sterno)
Other:
Flumazenil (Romazicon), Disulfiram (Antabuse), Acamprosate (Campral), Baclofen, Naltrexone, Fomepizole (Antizol)

Question 2

Dose related progression of drug effects

Answer 2

Sedation
Disinhibition
Ataxia
Sleep
Coma
Death

Question 3

Inverse Agonist

Answer 3

B-Carboline Carboxyethyl Ester

Binds to receptors to reduce GABA mediated Cl- conductance. Results in anxiety and muscle spasms and proconvulsant state

Question 4

Short acting Benzos

Answer 4

Prototype: Triazolam - half life of 3 hrs

Metabolized to alpha-hydroxytriazolam (active metabolite) then Glucuronidation, then excreted in urine

Used to treat sleep disorders in the absence of anxiety; hangover free sleep.

Question 5

Long acting Benzos

Answer 5

Prototype: Diazepam - half life of 30 hrs

Metabolized to Oxazepam (active metabolite) then Glucuronidation, then excreted in urine

Provides steady state drug concentration in CNS

Question 6

Tolerance

Answer 6

Pharmacodynamic changes happen in the brain make drug less effective. Flumazenil can send chronic users into withdrawal.

Question 7

NBRAs

Answer 7

Zolpidem (Ambien)
Eszopiclone (Lunesta)

Short acting hypnotics
Rapid absorption, no active metabolites

Binds to subtypes of benzo receptors and facilitate GABA mediated Cl- conductance. Can be reversed by Flumazenil

Question 8

Zolpidem (Ambien)

Answer 8

Relatively selective for type 1 Benzo receptors
Half life of 2.6 hrs
No hangover
No noticeable effects on REM sleep

Question 9

Eszopiclone (Lunesta)

Answer 9

Sedative hypnotic indicated for chronic treatment of insomnia
Rapid onset with half life of 6 hrs
Binds all 3 receptor types
No evidence of diminished efficacy over 6 month trial

Question 10

Cross Tolerance

Answer 10

Observed between benzos and other sedative-hypnotic drugs

Question 11

Ethanol mg%

Answer 11

80 mg% = legal driving limit
180-400 mg% = depression of cerebellum and loss of motor control
350-600 mg% = depression of midbrain function, spinal reflexes, depression of medullary respiratory control

Question 12

Ethanol Mechanisms

Answer 12

Dissolves in lipid bilayer reduce viscosity and function
Increases GABA-mediated Cl- conductance through GABA-A receptors
Decreases glutamate-mediated cation conductance through subtype NMDA receptors
INcreases serotonin-mediated conductance through 5HT3 receptors on inhibitory interneurons

Question 13

Ethanol Metabolism

Answer 13

NAD+ = dependent on alcohol dehydrogenase
NADPH = dependent on microsomal ethanol oxidizing system

Both routes form acetaldehyde -> acetate

Question 14

Effects of chronic ethanol ingestion

Answer 14

Peripheral neuropathy
CNS deficits - dementia
ventricular enlargement from more CSF (brain shrink)
Decrease white matter
Neuronal loss
Shrinkage of neuronal nuclei

Ethanol Neurotoxicity - decrease of myelination
Wernicke-Korsakoff syndrome due to thiamine deficiency
Hepatic encephalopathy from fat deposits in liver

Question 15

Teratogenicity

Answer 15

Fetal Alcohol Syndrome

Question 16

Drug interactions of Ethanol

Answer 16

Potentiates CNS depressant and respiratory of other sedative-hypnotic drugs

May cause GI bleeding when combined with aspirin or other anticlotting drugs

Liver damage when combined with Acetaminophen

Reduction in activity of some antibiotics

Question 17

Pharmacological treatment of alcoholism

Answer 17

Disulfiram (Antabuse) - inhibits aldehyde dehydrogenase - negative reinforcement

Naltrexone - decreases rewarding effects of alcohol

Acamprosate (Campral) - reduces glutamate neurotransmission and relapse in detoxified patients

Baclofen - GABA-B receptor agonist - decreases withdrawal symptoms

Question 18

Methanol

Answer 18

Metabolized to formaldehyde by alcohol dehydrogenase which is metabolized to formic acid by aldehyde dehydrogenase (highly toxic)

Treat methanol poisoning with Ethanol or Fomepizole (inhibitor of alcohol dehydrogenase)