Lecture 11 - Anxiolytics & Hypnotics Flashcards
BZDs with long half-lives
chlordiazepoxide diazepam pazepam clorazepate flurazepam
BZDs with short half-lives
lorazepam and oxazepam (without active metabolites)
alprazolam and triazolam ( with active metabolites)
Flumazenil is a ?
BZD antagonist
Thiopental is a ?
barbiturate
Buspirone is a ?
other anxiolytic
Zopiclone is a ?
other hypnotic
Anxiolytics provide ?
- calming effects
- relief of anxiety
Hypnotics provide ?
- promote drowsiness
- promote onset and maintenance of sleep
Describe the chemical classification:
A
BZDs
Describe the chemical classification:
B
barbiturates
Describe the chemical classification:
C
others
What drugs are included in classification A: BZDs?
alprazolam oxazepam chlordiazepoxide diazepam lorazepam triazolam
Describe the BZD basic foundation
benzene ring fused with a diazepine ring
What drugs are included in classification B: Barbiturates?
thiopental
pentobarbital
Describe the basic structure of barbiturates
all of the barbiturates are related to the structure of barbituric acid
What drugs are included in classification C: others
busprione zopiclone ethanol chloral hydrate antihistamines ramelteon
What is the action site of pharmacological mechanisms of BZDs?
GABA-A receptor
Describe GABA-A receptor
-GABA is the primary inhibitory neurotransmitter in the brain
Describe GABA-A subunits
- 2 alpha subunits
- 2 beta subunits
- 1 gamma subunit
Alpha subunit has 5 isoforms with alpha 1-5:
Describe them
alpha 1 = hypnotic
alpha 2-5 = sedation, psychomotor effect
GABA-A receptor = _____ channel
chloride
Describe the activation of GABA-A receptor
activation - chloride influx, hyperpolarizes neurons and decreases neuronal activity
How do BZDs work to interact with GABA-A receptors?
- BZDs bind to GABA-A receptors - enhance GABA actions and reduce excitability of neurons
- increases frequency of channel-opening events
- act as CNS depressants
Describe affinity of BZDs for GABA-B receptors
low affinity
How do barbiturates work to interact with GABA-A receptors?
- barbiturates bind to GABA-A receptors
- increases duration of channel-opening events
- GABA-mimetic at high concentration
- inhibit glutamate AMPA receptor
Describe general concept of pharmacokinetics
(what the body does to the drug)
absorption
distribution
metabolism
excretion
see slide 11
Define: onset
the time required for drug to be effective after administration
What does lipophilicity of drugs affect?
onset of action
More lipophilic = ?
more rapid onset of action
Define: duration
the amount of time that a measurable drug effect persists
Define: biotransformation (affects duration of action)
- microsomal oxidation (cytochrome P450 isozymes: phase 1 rxns)
- conjugation (phase 2 rxns)
- metabolic conversion to more water-soluble metabolites is required for clearance for CNS drugs from the body
What affects onset?
lipophilicity
What affects duration?
biotransformation
Describe lipophilicity of BZDs
triazolam > diazepam > lorazepam, oxazepam
Describe onset of BZDs
triazolam > diazepam > lorazepam, oxazepam
The main differences between BZDs are ?
rate of onset and duration of actions
BZDs: therapeutic uses relate to half life:
short acting is preferable for ______
hypnotic (to treat insomnia)
BZDs: therapeutic uses relate to half life:
long acting is preferable for ______
anxiolytic (to treat anxiety)
BZDs with long half life = ?
cause cumulative effects with multiple doses
there is overlap of drug in your system
BZDs are excreted from the _____.
kidney
Can BZDs cross placenta?
yes
*may inhibit CNS development of fetus
Can BZDs be detected in breast milk?
yes - therefore a risk to breastfeeding infants
Other than pregnant and breastfeeding patients, what other types of patients do BZDs pose a risk to?
- older patients, patients with liver diseases
- obese patients, redistributed to adipose tissue
Barbiturates are ______
lipophilic
*therefore they are absorbed and distributed rapidly
Barbiturates are metabolized in the ____
liver
______ are hepatic Cyt-P450 system inducers
Barbiturates
Duration of action for ultra short acting barbiturates
30 mins
Example of an ultra short acting barbiturate
thiopental - used for induction of anesthesia
Duration of action for short acting barbiturates
18-48 hours
Example of a short-acting barbiturate
secobarbital and pentobarbital - for hypnotic and sedative
Duration of action for long acting barbiturate
4-5 days
Example of long -acting barbiturate
phenobarbital - for seizures
List 6 therapeutic uses of BZDs
1-treats anxiety
2-treats insomnia
3-sedation and amnesia before and during surgical procedures
4-treats epilepsy and seizure states
5-muscle relaxation in specific neuromuscular disorders
6-control of ethanol withdrawal symptoms or other sedative-hypnotic withdrawal states
For relief of anxiety, BZDs act as a ______
sedative
List some anxiety disorders
- generalized anxiety disorder (GAD)
- panic disorder
- social phobia
- post-traumatic stress disorder (PTSD)
- obsessive-compulsive disorder (OCD)
List some general symptoms of anxiety disorders
- feelings of panic, fear and uneasiness
- uncontrollable, obsessive thoughts
- nightmares
- insomnia
- cold or sweaty hands/feet
- shortness of breath
- palpitations
- dry mouth
- numbness or tingling in hands or feet
- nausea
- muscle tension
- dizziness
How are BZDs used in anxiety?
used for the management of acute anxiety states and for rapid control of panic attacks
What is the first choice treatment for long-term management of GAD (generalized anxiety disorder) and panic disorders?
SSRIs
______ for panic disorders and agoraphobia
Alprazolam
For treatment of insomnia, BZDs act as a _____
hypnotic
symptoms of insomnia
- trouble falling or staying asleep-leads to sleep deprivation
- lying awake for a long time before falling asleep
- sleeping for only short periods
- being awake for much of the night
- waking up too early
Describe the physiology of sleep
NREM (non-rapid eye movement) (Stage 1-4)
and
REM (rapid eye movement)
Stage 1 of NREM sleep
light sleep during which the muscles begin to relax
Stage 2 of NREM sleep
brain activity slows down and eye movement stops
Stages 3/4 of NREM sleep
deep sleep during which all eye and muscle movement ceases
REM sleep
paradoxical sleep, rapid eye movement where most muscles are paralyzed
Do you just go from NREM to REM as you sleep?
No - you bounce back and forth between NREM and REM over your sleep period
How do BZDs work as hypnotics?
- decrease the latency to sleep onset and increase Stage 2 of NREM
- decrease both REM and slow sleep
For falling asleep, use _______ drug
fast acting, but shorter duration
ex. triazolam
For frequent awakenings, what type of drug would you use?
since falling asleep is not the problem, you would use a drug of medium duration
ex. lorazepam
Do you start benzos with high or low doses?
low doses obvs (eye roll like kelsey)
What are first choice of benzos for before and after surgery?
midazolam
lorazepam
How do BZDs work for before and after surgical procedures
- produce sedative effects
- cause anterograde anmesia (loss of ability to create new memories) - so you don’t remember the surgery
Are BZDs anesthetics?
nope - but used in conjunction with anesthetics
Which 2 BZDs are used for epilepsy and seizure states?
lorazepam and diazepam
Can BZDs help with management of seizures such as generalized tonic-clonic status epileptics, absence seizures, partial seizures, etc. ?
Yes
BZDs can also be used as a ____ relaxant - for muscle relaxation in skeletal muscle spasms caused by CNS disorder
muscle
ex. diazepam as a muscle relaxant
How can BZDs be used for withdrawl symptoms?
- can substitute for alcohol or other sedative-hypnotics during withdrawal states
- reducing the risk of withdrawl-related seizures
What is more powerful for CNS depression:
barbiturates or BZDs?
barbiturates
Therapeutic uses for barbiturates?
- Rarely used as a sedative and hypnotic. These drugs have largely been replaced by SAFER agents such as BZDs for the treatment of anxiety and insomnia.
- They are however, used as an anticonvulsant in epilepsy and seizure
- Barbituates (phenobarbital) are used as treatment of generalized tonic-clonic seizures but they are not the drug of first choice
Barbituates can also act as a component of ??
balanced anesthesia
- barbiturates such as thiopental can produce anesthesia (loss of feeling or sensation)
- enhance inhibitory neurotransmission
- inhibit excitatory neurotransmission
Describe thiopental
- used to induce anesthesia, often followed by inhalation agent
- rapid induction of anesthesia (30-40 sec rapid clearance)
- rapid redistribution from brain (short duration)
- anesthetic, but not analgesic
Describe the adverse effects of BZDs
CNS depression: drowsiness, confusion, anterograde amnesia, dizziness, lethargy, ataxia (these effects may persist and cause “hangover” or residual daytime effects)
When are benzo’s not safe?
when used in combination with other CNS depressants (ex. alcohol, opiates)
Define: tolerance
decreased responsiveness to a drug following repeated treatment
BZD tolerance is ______ tolerance
pharmacodynamic (has been associated with down-regulation of brain BZD receptors
Define: dependence
an altered physiologic state that requires continuous drug administration to prevent withdrawal symptoms
BZD withdrawal symptoms
relapse or rebound anxiety, insomnia, restlessness
Severity of BZD withdrawal symptoms is related in part to _______
half-life
- withdrawal symptoms are more common and more severe in patients on BZDs with short half lives vs. long half lives
ex. triazolam vs diazepam
Causes and risk factors of abuse potential of BZDs
- women
- elderly
- environmental factors (low socioeconomic status, unemployment, stress, over adherence…)
Contraindications
myasthenia gravis narrow-angle glaucoma alcoholism severe sleep apnea pregnant or nursing mothers
What is Flumazenil used for?
used to reverse the CNS depressant effects of BZD overdose
Flumazenil is a ??
BZD competitive antagonist
Does Flumazenil inhibit the effects of other sedative-hypnotics?
no - just benzos
How is Flumazenil given?
IV - acts rapidly and has a short half-life (0.7-1.3 hours)
When is Flumazenil a caution?
if BZDs given for seizures
Adverse effects of barbiturates?
- CNS depression
- can cause cardiac and vascular depression
- therapeutic index is low
- not safe
- barbiturates are less safe than BZDs
- metabolic and pharmacodynamic tolerance
- physical dependence with more severe withdrawal symptoms
What is a common reason to abuse barbiturates?
is to counteract the symptoms of other drugs
Barbiturate withdrawal symptoms
restlessness insomnia weakness dizziness nausea sweating anxiety (similar to BZD withdrawal symptoms)
see slides 36-39: good review slides
yayayayaya
Action site of Buspirone (anxiolytic)
- acts as a partial agonist at serotonin 5-HT1A receptor
- acts as a presynaptic antagonist at the presynaptic dopamine D2 receptor
- does not bind GABA receptors
Pharmacokinetics of Buspirone
- is rapidly absorbed orally
- undergoes extensive first-pass metabolism to form several active metabolites.
- elimination half-life of buspirone is 2-4 hours
- takes more than one week to produce therapeutic effects
Therapeutic use of Buspirone
anxiolytic
-effects take more than 1 week to develop: unsuitable for management of acute anxiety states
-good for management of anxiety disorders but not good for panic disorders (due to the long onset)
- no hypnotic effect
- causes less psychomotor impairment than BZDs and does not affect driving skills
- has no anticonvulsant properties
- has no muscle relaxant properties
Adverse effects of Buspirone
-tachycardia, palpitations, dizziness, and others may occur
Is there a risk of tolerance and dependence with Buspirone?
no
- minimal abuse potential
- no withdrawal effects
- no potentiation of CNS depression caused by other sedative-hypnotics and ethanol
Consideration with Buspirone?
do not use with monoamine oxidase (MAO) inhibitors
What are the Z drugs?
zopiclone (Imovane)
zolpidem (Sublinox)
Action site for Zopicole?
- zopiclone targets GABA-A receptor and is specific for alpha 1
- enhances GABA-mediated neuronal inhibition
Zopiclone is ______
lipophilic - rapidly absorbed and peak plasma concentrations occur within 1-2 hours.
Zopiclone is rapidly _____
metabolized - by cytochrome P450s
half life of zopiclone ?
3-5 hours
Therapeutic use of zopiclone
Not for anxiety
Used for insomnia
-short term treatment of insomnia
-increases total sleep time, mainly via increases in stage 2 NREM sleep
-more effective than BZDs because tends to increase stage 3 and 4 sleep
Causes less amnesia
Minimal muscle relaxing effects
Minimal anticonvulsant effects
Adverse effects of Zopiclone
- drowsiness
- memory impairments
- dizziness and fatigue
Is there a low or high risk for tolerance and dependence of zopiclone?
low risk (over a 6 month period)
What is zopiclone antagonized by?
flumazenil
