EXAM 4 Sedatives Dr. Pond Flashcards
What is the difference between sedatives and hypnotics?
Sedative reduces anxiety (anxiolytic
Hypnotics reduce the onset and improve the maintenance of sleep
-a d can drug can be used as a sedative at a low dose, and as a hypnotic at a higher dose
Which drugs have a linear relationship between the dose and sedative-hypnotic effect
Barbiturates: the higher the dose, the more it goes from a sedative to a hypnotic -> up to coma and death
Benzos is not as linear and safer
Which areas of the brain are involved in causing anxiety?
-Amygdala - associated with fear
-Hippocampus - mood, emotion, memory
so when experiencing something that caused fear that memory context becomes activated too
Which structure communicates with both
Raphe nuclei: contain serotonergic cell bodies in the brain stem
->connected to the Brainstem, hypothalamus and vagus
->causing physical symptoms:
-increased respiration
-increase in NE (fight or flight)
-activation of HPA axis -> cortisol
-increase in BP and HR
What is required for benzos to have sedative-hypnotic activity?
a substituent at postion 7
ex: nitrazepam, clonazepam (Klonidin), temazepam (Restoril)
Which benzo produces profound anterograde
amnesia when used with alcohol?
Flunitrazepam “Roofies”
How are benzos metabolized?
-Metabolized via microsomal enzymes in the liver
-glucuronidation only
-Liver is the only means of elimination
Which benzo has the shortest onset?
Diazepam
-but long half-life (20-50hr)
Which benzos have a slow onset?
Temazepam
Oxazepam
Which benzos form metabolites?
-Chlordiazepoxide
-Diazepam
others don’t have active metabolites
Which benzos have low risk of withdrawal?
-long half-life -> it stays arround and tapres itself
-actvite metabolites
-Diazepam
high risk: Chlordiazepoxide, Alpralzolam, Lorazepam, Oxazepam
Benzos with short-half-life
Lorazepam
Oxazepam
Temazepam
Which benzos are metabolized by phase II glucuronidation only?
-Lorazepam
-Oxazepam
-Temazepam
What type of channel is the GABA(A) receptor?
ion-channel: Cl(-)
Which subunits of the GABA(A) receptor are targets?
α subunit: GABA
ß subunit: Benzos
must include at least 1 γ2 subunit (most abundant
in limbic and neocortical regions – emotions, memory)
What is the role of Flumazenil?
-Benzodaizepine antagonist
-Used for reversing CNS depression (benzo overdose)
What is the MOA of ß Carbolines?
inverse agonist of GABA(A) receptors
-bind to GABA(A) but have the opposite effect
->excitatory: can cause anxiety and seizures
What is the MOA of Buspirone (Buspar)?
Pre- and postsynaptically: INHIBITORY
5-HT1A Full agonist at Raphe Nucleus
5-HT1A partial agonist at the Hippocampus and Amygdala
What is the role of Barbiturates in therapy?
-anesthesia induction
-seizures
-inducing coma after head trauma
What to be cautious about with barbiturates
-low therapeutic index
-high abuse potential and physical dependence
-tolerance to sedative but not toxic effects
-often used for suicide
MOA of barbiturates
-Interact with all types of GABA(A) receptors
-GABA(A-R) agonist at high concentrations
-AMPA-R antagonist: activated by glutamate, excitatory
MOA of Partial allosteric modulators PAMs
Zolpidem (Ambien)
Zaleplon (Sonata)
Eszopiclone (Lunesta)
-Similar to benzodiazepines but only bind to GABA(A) receptor isoforms with α1subunits
-predominantly used in insomnia
Which of the PAMs have the shortest half-life?
Zaleplon: 1hr
-Zolpidem: half life ~ 2 hrs
-Eszopiclone: half life 6 hr
Where is Melatonin produced?
Pineal Gland
promotes sleep -> binding MT1, MT2 receptors
Where is Orexin produced?
Lateral Hypothalamus
Orexin A and Orexin B
promotes wakefulness -> binding OX1R, OX2R
MOA of Ramelteon (Rozerem)
MT1 and MT2 agonist
-helps with falling asleep
-forms active metabolites
ADE:
dizziness, drowsiness, fatigue, nausea
MOA of Tasmelteon (Hetlioz)
-Melatonin receptor agonist (MT2 > MT1)
-used for non-24 hr sleep/wake cycle
-metabolites have minimal activity
ADE:
-headache, dream disorder
-UTIs, upper respiratory infections
-alanine aminotransferase levels may be elevated
What are the Orexin receptor antagonist
[orexant]
-Suvorexant
-lemborexant
-daridorexant
What type of receptors are Orexin A and Orexin B?
metabotropic
found pre and postsynaptically
Which drug is used for narcolepsy and cataplexy?
Sodium oxybate (Xyrem)
MOA of Sodium oxybate (Xyrem)
-Weak agonist at GABAB receptors, high affinity for GHB receptor
-Gamma hydroxybutyrate (GHB) salt
ADE:
-dizziness, somnolence
-CNS/respiratory depression & abuse!
-tremor
-N/V
-urinary incontinence,
-confusion, sleep-walking
-depression/suicide risk
