504-2 Cns Depressants

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504-2 CNS DEPRESSANTS

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504-2 CNS DEPRESSANTS

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Dose related progression of effects of barbituates?

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It's a linear relationship that can lead to death.

NOTE: Benzo levels out at sleep level.

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Mechanism of action for benzo?

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Potentiate the action of GABA at the GABA-A receptor.

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Agonist of benzo?

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Enhance GABA-mediated Cl conductance and neuronal inhibition.

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Antagonist

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Bind to benzo receptor and competitively block the effects of benz agonists on GABA-mediated Cl conductance and neuronal inhibition.

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Inverse agonist

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Bind to benzo receptor and reduce GABA-mediated Cl conductance and neuronal inhibition, resulting in anxiety, muscle spasms, and proconvulsant state.

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Benzo fall into two general classes:

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Short acting

Long acting

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Short acting usefulness

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For Tx sleep disorders

i.e. triazolam

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Long acting

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Provides steady state drug [ ] in the CNS.

Provide a constant calming effect.

i.e. diazopam

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Abrupt withdrawal of short vs.long acting benzo?

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Short acting: may lead to severe withdrawal symptoms.

Long acting: usually does not elicit severe symptoms, but can be precipitated by administration of flumazenil.

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Benzo and sleep stages

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Decrease stage 0 (wakefulness).

Increase time in stage 2 (major fraction of non-REM sleep).

Decrease stages 3 & 4 ( slow wave sleep)

REM time is shortened, but compensated by increase number of REM cycles.

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Classes of benzo

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Two general classes

1. short acting
2. long acting

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Short acting benzos

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Tx sleep disorders in absence of anxiety.

Prototype: triazolam

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Long acting benzos

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Provides steady state drug concentration in the CNS.

Useful for Tx of sleep disorders assoc with anxiety.

Prototype: diazepam

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Metabolism of benzo

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In the liver by microsomal oxidase system.

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Therapeutic uses of flumazenil

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Reversal of benzos

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Non-benzodiazepine receptor agonist (NBRA) prototype

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Zolpidem (Ambien)

Eszopiclone (Lunesta)

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Action of NBRA

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Bind to the benzo receptor on the GABA-A receptor.

Produce less muscle relaxation and anticonvulsant effects at hypnotic doses.

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Zolpidem

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Selective for Type I benzo receptor.

Useful for acute Tx of sleep disorders.

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Eszopiclone

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For chronic Tx of insomnia

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Most sensitive CNS structures Ethanol exerts on?

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1. polysynaptic reticular activating system

2. cerebral cortex

NOTE: depression of these areas results in euphoria, disorganized thought, dulling of performance.

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What mg % of ethanol causes depression of cerebellum, resulting in loss of motor coordination?

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180-400 mg%

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.... depression of midbrain functions, spinal reflexes, and temp. regulation, and can also lead to coma?

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350-500 mg%

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.... depression of medullary centers and death?

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450-600 %mg

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What it the mechanism of action of ethanol?

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Dissolves in lipid bilayer--> disrupting protein function.

Increases BABA-mediated Cl conductance through the GABA-A receptor.

Dec. glutamate mediated cation conductance.

Increases serotonin mediated cation conductance thru 5HT3 receptors.

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Pharmacokinetics of alcohol

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1. rapid absorption. 30-90 mins to max. conc in blood.

2. 90-98% is oxidized

3. follows zero order kinetics

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What two enzyme system oxidize alcohol?

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1. NAD+ dependent alcohol dehydrogenase

2. NADPH dependent microsomal ethanol oxidizing system.

NOTE: both systems form acetaldehyde which is converted to acetate.

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Pharmacokinetic tolerance for alcohol

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1. inc alcohol dehydrogenase
2. inc synthesis of NAD+
3. MEOS activity

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PharmacoDYNAMIC tolerance for alcohol

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1. dec sensitivity to membrane fluidizing effects of ethanol.

2. dec GABA-A receptors

3. inc NMDA receptors

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Consequences of choronic ethanol ingestion

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1. CNS deficit
2. Wernicke-Korsakoff syndrome (thiamine deficiency)
3. cirrhosis
4. risk for cancer
5. acute and chronic pancreatitis

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Teratogenicity

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Fetal alcohol syndrome

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Treatment for alcoholism

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1. Disulfiram: inhibitor of aldehyde dehydrogenase
2. naltrexone
3. acamprosate
4. baclofen