Lecture 11 - Anxiolytics, Sedatives, & Hypnotics Flashcards
Which BZDs have long half-lives?
- Chlordiazepoxide
- Diazepam
- Prazepam
- Clorazepate
- Flurazepam
Which BZDs have short half-lives?
- Lorazepam and oxazepam (w/o active metabolites)
- Alprazolam and triazolam (w/ active metabolites)
What is the BZD antagonist? Is it competitive or non-competitive?
- Flumazenil
- Competitive b/c has a high affinity for BZD binding site
What is an example of a barbiturate?
Thiopental
What is an example of another anxiolytic?
Buspirone
What is an example of another hypnotic?
Zopiclone
What do anxiolytics do?
- Calming effect
- Relieve anxiety
What do hypnotics do?
Promote drowsiness and onset and maintenance of sleep
What is the basic foundation of BZDs?
Benzene ring fused w/ a diazepine ring
All barbiturates are related to the structure of ____
Barbituric acid
What is the action site of BZDs?
GABA-A receptor (primary inhibitory NT in the brain)
GABA-A receptor is a _____ channel
Chloride
What does activation of the GABA-A receptor cause?
Chloride influx, which hyperpolarizes neurons and decreases neuronal activity
What happens when a BZD binds to GABA-A receptor?
- Enhances GABA actions, so reduces excitability of neurons
- Increases frequency of channel-opening events
- Acts as a CNS depressant
What do barbiturates bind to?
GABA-A receptor
What is a barbiturate at high concentrations?
GABA-mimetic
What do barbiturates inhibit?
AMPA receptor
Which BZD is the most lipophilic?
Triazolam
Which BZDs are the least lipophilic?
Lorazepam and oxazepam
What affects the duration of action of BZDs?
- Microsomal oxidation (CYP phase 1 reactions)
- Conjugation (phase 2 reactions)
What is required for clearance of CNS drugs from the body?
Metabolic conversion to more water-soluble metabolites
The therapeutic uses of BZDs relates to _____
Half life
____ acting BZDs are preferable for hypnotic effects
Slow
____ acting BZDs are preferable for anxiolytic effects
Longer
BZDs are excreted from the ____
Kidneys
Can BZDs cross the placental barrier?
Yes
Can BZDs be detected in breast milk?
Yes
Where are barbiturates metabolized?
Liver
Barbiturates are ___ inducers
CYP
When would an ultra short-acting barbiturate be used?
Thiopental for induction of anesthesia
When would a short-acting barbiturate be used?
Secobarbital or pentobarbital for hypnotic and sedative effects
When would a long-acting barbiturate be used?
Phenobarbital for seizures
What are the therapeutic uses of BZDs?
- Relief of anxiety and treatment of insomnia
- Sedation and amnesia before and during surgical procedures
- Treatment of epilepsy and seizure states
- Muscle relaxation in specific neuromuscular disorders
- Control of ethanol withdrawal symptoms of other sedative-hypnotic withdrawal states
What are the first choice BZDs for sedation and amnesia before and during surgical procedures?
Midazolam and lorazepam
Which BZDs are used for treatment of epilepsy and seizure states?
Lorazepam and diazepam
Are BZDs the first choice for long-term epilepsy treatment?
No b/c can cause tolerance and dependence
Which BZD is used for muscle relaxation?
Diazepam
What are the first choice for long-term management of generalized anxiety disorders and panic disorders?
SSRIs
Which drug is used for panic disorders and agoraphobia?
Alprazolam
What is stage 1 of sleep?
Light sleep during which muscles begin to relax
What is stage 2 of sleep?
Brain activity slows down and eye movement stops
What is stage 3/4 of sleep?
Deep sleep during which all eye and muscle movement ceases
What is REM sleep?
- Rapid eye movement
- Most muscles are paralyzed
What effect do BZDs have on sleep?
- Decrease latency to sleep onset
- Increase stage of NREM
- Decrease both REM and slow wave sleep
Which BZD should be used for difficulty falling asleep?
- Fast acting but shorter duration
- Triazolam
Which BZD should be used for frequent awakenings?
- Drug of medium duration
- Lorazepam
Do BZDs or barbiturates have higher CNS depression?
Barbiturates
What is the therapeutic use of barbiturates?
- Anticonvulsant in epilepsy and seizure
- As a component of balanced anesthesia
Which barbiturate is used in the treatment of tonic-clonic seizures? Is it the first choice?
- Phenobarbital
- Not first choice
Which barbiturate is used to induce anesthesia?
Thiopental, often followed by inhalation agent
Are BZDs or barbiturates safer?
BZDs b/c bigger therapeutic index
Is there an antidote for barbiturates?
No
What are common adverse effects of BZDs?
Hangover-like symptoms (drowsiness, confusion, dizziness)
What should BZDs never be mixed w/?
Other CNS depressants like alcohol or opiates
What is pharmacodynamic tolerance?
Receptor de-sensitization, so you need an increased amount of drug to produce the same effect
What are some BZD withdrawal symptoms?
Relapse or rebound anxiety, insomnia, and restlessness
When are BZD withdrawal symptoms more common?
Px on BZDs w/ short half-lives
How long should BZDs be taken?
No more than 2 months
What are some contraindications of BZDs?
- Myasthenia gravis
- Narrow-angle glaucoma
- Alcoholism
- Severe sleep apnea
- Pregnant or nursing mothers
Do BZDs have any effect on CYP isoenzymes?
No
What can be caused by high doses of barbiturates?
Cardiac and vascular depression
What needs to be done when taking a px off BZDs?
Need to be tapered
What needs to be done when taking a px off barbiturates?
Give BZDs and then need to be tapered
What is given for BZD overdose?
Flumanezil
Is the onset of anxiolytic effects faster for BZDs or SSRIs?
BZDs
Can SSRIs cause dependence?
No
Do BZDs or SSRIs cause amnesic effects?
Only BZDs
What is the action site of buspirone?
- Partial agonist at serotonin 5-HT1A receptor
- Presynaptic antagonist at presynaptic dopamine D2 receptor
Is buspirone good for acute anxiety?
No, takes at least one week to produce therapeutic effects
Is the T 1/2 of buspirone long or short and why?
Short b/c undergoes extensive first pass metabolism
What is the therapeutic use for buspirone?
Generalized anxiety states
What should buspirone not be used w/?
MAO inhibitors
What is the action site of zopiclone?
- Targets GABA-A receptor; specific to alpha 1
- Enhances GABA-mediated neuronal inhibition
What is the therapeutic use of zopiclone?
- Short-term treatment of insomnia
- Increases total sleep time, mainly via increasing stage 2 NREM sleep
Why is zopiclone more effective than BZDs for insomnia?
Zopiclone tends to increase stage 3 and 4 sleep, while BZDs decrease it
Does zopiclone cause amnesia?
No
What is zopiclone antagonized by?
Flumanezil
Does zopiclone produce tolerance and dependence?
Low risk
