Neuro - Sedative-hypnotic drugs and alcohol

josisixo's version from 2016-05-29 13:32


Sedative-hypnotic drugs and alcohol
Question Answer
Benzodiazepines1. potentiate the action of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA) at the GABA-A receptor. 2. The resulting neuronal inhibition appears to be responsible for the pharmacological actions of benzodiazepines: reduced anxiety, sedation, hypnosis, muscle relaxation, and anti-convulsant activity
Short Acting benzouseful for treating sleep disorders in the absence of anxiety; rapid onset and elimination to induce sleep and prevent daytime hangover. = Triazolam
Long Acting benzoprovides a steady state drug concentration in the central nervous system to provide a constant calming, antianxiety effect = Diazpan
Diazepan(GABA agonist): enhances GABA-mediated Cl- conductance and neuronal inhibition
Benzo Tolerance and Physical Dependence1. Pharmacodynamic tolerance to the anti-anxiety and hypnotic effects of benzodiazepines develops with chronic use 2. Chronic use of benzodiazepines leads to physical dependence 3. Abrupt withdrawal of short-acting benzodiazepines may lead to severe withdrawal symptoms 4 .Abrupt withdrawal of long-acting benzodiazepines usually does not elicit severe symptoms, but a severe withdrawal syndrome can be precipitated in dependent individuals by adminstration of flumazenil
Flumazenil1. GABA antagonist 2. Binds to the bnezodiazepine receptor and competitively blocks the effects of benzodiazepine agonists on GABA mediated Cl- conductance and neuronal inhibition; have no effect alone.
Beta-carboline carboxyethyl ester1. GABA inverse antagonist 2. Binds to the benzodiazepine receptor and reduces GABA mediated Cl- conductance and neuronal inhibition, resulting in anxiety, muscle spasms, and a pro-convulsant state
Non-benzodiazepine receptor agonists (NBRAs)1. Mechanisms of Action: bind to subtypes of benzodiazepine receptor and facilitate GABA mediated Cl- conductance and neuronal inhibition.
zolipidem (Ambien)selective for type 1 benzodiazepine receptor. It is rapidly absorbed and eliminated with a half-life of 2.6 h.
Eszopiclone (Lunesta)has a rapid onset of action, but a longer half life (~6h) than zolipidem. Appears to bind to all three benzodiazepine receptor types; mechanism for selectivity unclear.
Zolipidem and Eszopiclone are antagonized byFlumazenil
Ethanol1. Dose related progression of CNS depression, similar to that observed with other sedative-hypnotic drugs 2. Most sensitive CNS structures are polysynaptic reticular activating system and the cerebral cortex (blood ethanol 40-150 mg%); depression of these areas results in euphoria, disorganized thought, and dully of performance 180-400 mg%: depression of cerebellum, loss of motor control, 350-600 mg%: depression of midbrain function, spinal reflexes, depression of medullary respiratory control
Ethanol Mechanisms of actionDissolves in the lipid bilayer of plasma membranes, reducing membrane viscosity and disrupting protein function 2. Increases GABA-mediated Cl- conductance through the GABA-A receptor 3. Decreases glutamate-mediated cation conductance through subtypes of NMDA receptors 4. Increases serotonin-mediated cation conductance through 5HT3 receptors located on inhibitory interneurons
Ethanol Pharmacokinetics1. Rapid absorption from intestines, stomach, and colon; time from last drink to maximal concentration in blood is 30-90 min. 2. Elimination: 90-98% is oxidized 3. Follows zero order kinetics (7-10 g/h; takes ~ 5h to metabolize 4 oz of Jack Daniels) 4. Oxidized by two enzyme systems: NAD+ dependent alcohol dehydrogenase, NADPH dependent alcohol microsomal ethanol oxidizing system (MEOS) - Both systems form acetaldehyde, which is converted to acetate by aldehyde dehydrogenase
Ethanol Tolerance/Dependence1. Pharmacokinetic tolerance (variable): increase production of alcohol dehydrogenase; increase synthesis of NAD+; increase MEOS activity 2. Pharmacodynamic tolerance (mechanism poorly understood): decrease sensitivity to membrane fluidizing effects of ethanol; decrease GABA A receptors; increase NMDA receptors
Short Acting benzo clinicalsleep disorders - Decrease the latency to onset of sleep, Decrease number of awakenings, Increase total sleep time, Decrease stage 0 (wakefulness), Increase time in stage 2 (major fraction of non-REM sleep), Decrease slow wave sleep (stage 3 and 4), Time in REM sleep is shortened, but this is compensated by an increase in the nuber of REM cycles, mostly late in sleep time
Long Acting benzo clinicalanxiety, muscle relaxation, anti-convulsant
Zolipidem clinicalacute treatment of sleep disorders - No morning hangover, Stage 3 sleep is usually preserved, effects on REM sleep are rare and inconsistent
Eszopiclone clinicalfirst sedative-hypnotic indicated for chronic treatment of insomnia
Benzo and NRBA general uses1. Treatment of anxiety 2. Panic attacks 3. Post-traumatic stress disorder 4. Treatment of muscle spasms 5. Treatment of spasticity associated with cerebral palsy and other spastic disorders 6. Treatment of convulsive disorders (status epilepticus) 7. Treatment of sleep disorders 8. Treatment of sedative-hypnotic withdrawal symptoms 9. Pre- and co-anesthesia 10. Relaxation for endoscopic procedures 11. Re-entrainment of circadian rhythms
Flumazenil clinical1. Used for treatment of benzodiazepine or NBRA overdose 2. Used to hasten recovery from sedation when a benzodiazepine is used therapeutically
Disulfiram (antabuse) for alcohol abuseinhibitor of aldehyde dehydrogenase
Naltrexone for alcohol abusedecreases the rewarding effects of alcohol
Acamprosate (campral) for alcohol abusereduces glutamate neurotransmission – reduces relapse in detoxified patients
Baclofen for alcohol abuseGABA-B receptor agonist – decreases alcohol withdrawal symptoms and promotes abstinence; reduces alcohol-related anxiety and craving
Methanol intoxication Treatment1. Treat with ethanol 2. Treat with Fomepizole (Antizol: inhibitor of alcohol dehydrogenase) 3. Correct the metabolic acidosis