Sedative Hypnotics and Anxiolytics Flashcards
Stress versus anxiety
stress is something that happens to you and anxiety is a reaction to stress that the brain produces
Amygdala
part of the limbic system; ancient, primitive structure; conditioned fear in rodents; anxiety in humans
Anxiety disorders
GAD; phobias; OCD; eating disorders; panic attacks; mixed anxiety-depression; PTSC
Sedation
reduced responsiveness, calming effect
hypnosis
drug-induced sleep
Anesthesia
drug-induced amnesia, analgesia, unconsciousness, lsot muscle tone
Coma
unconsciousness for 6+ hours, no sleep cycles, non-responsive to pain, light/sound
Major inhibitor neurotransmitter in the CNS
GABA
What is GABA produced from
glutamate
GABA activates
GABAA type ligand gated Cl- channels, and GABAB and GABAC receptors which are GPCRs
Most sedative/hypnotics act at which receptors
act at the GABA-A receptor complex (ligand-gated chloride channel) through via different pharmacological mechanisms
How many GABA molecules are required to bind and activate a GABA-A receptor?
2 GABA molecules
Cl- influx through the GABA receptor does what to the cell membrane?
hyperpolarizes the cell membrane
Where do benzodiazepines bind?
at a site distinct from the GABA binding site
What does binding of a BZD molecule enhance?
enhances the activity of GABA in activating the receptor, but binding of BZD has no activity on its own
What type of binding does BZDs exhibit?
allosteric
How does the addition of a BZD or barbiturate when GABA is present enhance the action of GABA?
BZD largely increases the frequency of channel openings whereas barbiturates increase the duration of openings
What do molecules with inverse agonist action at the BZD site do when they bind to the BZD site?
they make it harder for GABA to open the channel (negative allosteric modulation), which is the opposite of what BZDs do
What is a GABA(A) receptor agonist
an agonist at the GABA binding site
What does a BZD site agonist do?
facilitates the action of GABA
What does a BZD site antagonist do?
antagonizes the action of BZD agonists without antagonizing the action of barbiturates
What is a BZD site inverse agonist
negative allosteric modulator of GABAAR function
Benzodiazepines
- Alprazolam
- Flurazepam
- Midozolam
- Flumazenil
How do benzodiazepines work?
potentiate GABA throughout the CNS
Metabolism of benzodiazepines
extensively metabolized with many active metabolites
What are benzodiazepines potentiated by?
potentiated by other CNS depressants as well as alcohol
What is the potential risk associated with benzodiazepines?
significant potential for psychological and physical dependence - people can become addicted to drugs such as Xanax and sleep pills
Clinical use of Midazolam
for acute seizure control, pre-surgery anxiolysis, amnesia and sedation;
rapid onset, fast recovery
Clinical use of Alprazolam
mainly for panic, GAD;
rapid acting, moderate duration
Clinical use of Flurazepam
long duration, next-day sedation is possible;
for insomnia and those who need help maintaining sleep
Metabolism of Benzodiazepines
CYP3A4 and CYP2C19
Adverse effects of benzodiazepines (largely apply to barbiturates as well)
- Amnesia (short-acting benzos)
- Daytime sedation (long-acting benzos)
- Respiratory/CV depression (esp in pts with pulmonary disease)
- Withdrawal (anxiety, insomnia, CNS stimulation, convulsions)
- Dependence
- Potentiated by P-450 inhibitors
MOA of Flumazenil
Simple antagonist at the allosteric site (neither negative or positive modulator); can compete for binding at the BZD site with a positive allosteric modulator and therefore antagonist its own action
Psychologic dependence
compulsive use
Physiologic dependence
continued drug use to prevent withdrawal
Tolerance
decreased responsiveness to fixed dose; increase dose to maintain effect
Barbiturates induce
P450s
Why is overdose easier to achieve with barbiturates than with benzos?
barbiturates have stronger action at GABA-A, the ability to directly open GABA receptors, and actions at other NT systems
Use of barbiturates
rarely for seizures, anesthesia; commonly for severely brain injured patients to induce coma in order to bring down ICP following an injury
Which barbiturate is used for the death penalty
pentobarbital
Barbiturate overdose
coma, respiratory depression, death
Buspirone
5-HT1A receptor partial agonist; less sedation; little or no withdrawal syndrome; low abuse potential
Clinical uses of Buspirone
GAD, not panic disorders
Types of insomnia
- Transient (~3 days)
- Short-term (3-21 days)
- Long-term (>21 days)
- Rebound
What is rebound insomnia?
withdrawal insomnia due to drug discontinuation, possibly worse than original insomnia, occurs most with short-acting agents, avoid by titrating down
How do you treat transient insomnia with sedatives?
smallest efficacious dose for the shortest time possible (2-4 days)
How do you treat short term insomnia with sedatives?
due to personal stress (grief, illness), only use drugs for 7-10 days
Why do you use BZD and Z compounds instead of barbiturates for insomnia?
efficacy is the same with less adverse effects/risk; Z compounds associated with less day-after sedation; better formulation options
Why is rebound insomnia more common in drugs with a short half life?
they wear off quicker, making it more likely that you will be in a state of withdrawal the next day; more likely to be exposing the state where there is increased excitability due to adjustment of GABA-A receptor levels
Who is more likely to be at a risk for liver issues that can disturb the metabolism of hypnosedatives?
elderly people - can lead to overdose or adverse effects
Non-Benzodiazepine “Z” compounds act where
at the BZD site like BZDs
What are Z compounds more selective for
alpha1-containing receptors
Why are the effects of Z compounds more mild and not as sedating as BZDs?
because Z compounds are more selective for alpha1-containing receptors
What is possible with high doses and prolonged use of Zolpidem?
dependence
Non-benzodiazepine “Z” compounds
- Zolpidem
- Zaleplon
- Eszopiclone
Ramelteon is selective for
MT1 and MT2 receptors, not MT3 receptors
What is Ramelteon?
melatonin mimetic; acts in suprachiasmatic nucleus to promote sleep; no action at GABAa
The suprachiasmatic nucleus is involved in regulating
circadian rhythms
Stages of sleep
Stage 1: somnolence, drowsy, transition
Stage 2: sleep spindles, K complexes, unconsciousness
Stage 3/4: “deep” sleep
REM: “paradoxical” sleep
What happens in Stage 1 sleep?
transition stage from wakefullness to sleep
What happens in Stage 2 sleep?
electrophysiological characteristics define stage 2 as spindles and K complexes
What happens in REM sleep?
dreams, rapid eye movements, paralysis (probably beneficial)
BZD/Barbs effect on sleep stages
increase Stage 2; decrease REM; decrease stage 3/4
Z compounds effect on sleep stages
increase or maintain stage 2; decrease or maintain REM
