benzodiazepines Flashcards
what is anxiety?
a common psychiatric disorder found and most people who have anxiety, they have a comorbid disorder
2x more likely in women than men
how has the DSM-5 reclassified anxiety disorders?
into 3 classes:
Anxiety disorders
Obsessive-compulsive disorder (OCD) and related disorders
Trauma related disorders, including post-traumatic stress disorder (PTSD)
what are ways anxiety expressed?
- panic episodes
- phobic avoidance of anxiety-eliciting stimuli
- intrusive thoughts or compulsive behaviors
- damaging negative thinking patterns
is fear and anxiety the same?
NO
Fear: emotional response to current threat
Anxiety: apprehension about possible future events
what could anxiety be a result of in the brain?
an imbalance between emotion generating centers & higher cortical controls
for example:
- Amygdala : emotion - fear
| - Hypothalamus : emotion - activates sympathetic and produces stress response
| - Periaqueductal grey (PAG): emotion - pain and feelings of dread
| - Hippocampus: emotion - memory of fear
| - PFC: higher cortical - uses logic to make judgements and decisions
what is a NT other than serotonin found in anxiety?
GABA
how does GABA act in anxiety?
Impaired GABA function leads to overactive amygdala activity - menacing or dread feelings
GABA receptors found in HIGH concentrations in amygdala, limbic system, & cerebral cortex so we have the ability to shut down our circuit if we get too anxious.
what are the 2 drug groups that are given for anxiety disorders? what do they do?
- anxiolytics: Relieve tension, worry, stress
produce a calm and relaxed state - sedative - hypnotic: drugs are CNS depressants and include barbiturates, benzodiazepines, & alcohol - aides in sleep and sedation
- what are the use of barbiturates?
- what schedule are they?
- what is their route of admin?
- what is their absorption?
- what is their distribution?
- surgical anesthesia, sleep aid, anti-anxiety, anticonvulsant
- 2, 3, 4 - ex. pentobarbital = schedule II; butobarbital = III; luminal = IV
- Oral or IV most common
Short-term use: IV
Long-term use: oral
Intranasal common route for barbiturate abuse - Absorbed rapidly from GI tract depending on lipid solubility
Ultrashort acting = highest lipid solubility
Long acting = lowest lipid solubility - Readily pass through BBB & placental barriers, detectable in milk of nursing mothers
and accumulates in skeletal muscles and adipose tissue (depot binding!)
- what is the metabolism of barbiturates?
- what metabolites are formed?
- how is it excreted?
- broken down in the liver (CYP450 enzymes).
- inactive metabolites
- excreted in urine
what occurs with chronic repeated use of barbiturates?
- metabolic tolerance, cross tolerance, behavioral tolerance
CYP450 enzyme induction associated with increased drug metabolism, lower blood concentration of drug, and reduced drug effectiveness.
how do barbiturates act in the CNS?
- enhance GABA actions
- acts as positive allosteric modulator : increase Increase affinity of the GABAa receptor for GABA
- directly open Cl- ion channel in GABAA receptor without GABA present - causing chances of extreme sedation
- at high doses: antagonists for NMDA, AMPA and Kainate glutamate receptors
what does NOT show tolerance in barbiturates?
Respiratory depression does NOT show tolerance
LOOK at graph on slide 10
what type of dependence does barbiturates cause? what does this implicate
physical dependence so…
- high potential for abuse
- cannot quit cold turkey
Withdrawal syndrome associated with
potentially fatal rebound hyperexcitability
in brain -Similar to alcohol
what effects do we see with high dose of barbiturates?
Poor coordination, slurred speech, life-threatening respiratory depression
what are benzodiazepines used to treat?
anxiety disorders
what are trade names for benzodiazepines?
valium, xanax
what is important about the use of benzodiazepines?
account for ~2/3rds of all medical prescriptions for psychoactive drugs
most are for anxiety and panic disorders
what type of schedule drugs are benzodiazepines?
schedule 4
what is the common suffix for benzodiazepines?
End with suffix azolam or azepam
what are the classes of benzodiazepines and what are their functions?
- Ultrashort-acting
use: IV anesthetic/ surgical preanesthetic
ex: Midazolam (Versed) - Short-acting
use: anxiety disorders/ insomnia
ex: alprazolam (Xanax) & lorazepam (Ativan) - Long-acting
use: chronic anxiety, seizures, or alcohol n
withdrawal
ex: Diazepam (Valium)
how long do people use benzodiazepines?
- women use it more than men
- 80% use it for 4 months or less
- 45% use it for less than a month
- 15% use it for more than a year
- what is the route of admin?
- what is the absorption?
- what is the distribution?
- Oral (most common; xanax),
IV, IM injections (Ativan; Valium)
Intranasal common during abuse (crushed up & snorted - Onset of action determined by lipid solubility
Short-acting BDZs generally more lipid-soluble and reach brain faster than long-acting BDZs
- High blood albumin protein binding (depot binding)
Redistribution from fat & muscle can extend time drug can be detected in a person’s system
what is the metabolism of benzodiazepines?
Short-acting BDZs like lorazepam (Ativan) metabolized in 1 step into INACTIVE metabolites
Ativan: half-life 12 hours
Long-acting BDZs like chlordiazepoxide(Librium) or Diazepam (Valium) metabolized in liver in multiple steps
Valium half-life: ~48 hours
Produce ACTIVE metabolites that re-enter
circulation
Major active : nordiazepam
Minor active: temazepam
what is the difference between benzodiazepines and barbiturates?
BDZs do not induce CYP liver enzymes
Less risk for metabolic tolerance (behavioral tolerance still occurs)
what do benzodiaepines do in the brain?
- Positive allosteric modulator of GABAA receptor - enhance GABAA receptor activity by up to 700%!
- Benzodiazepines also increase actions of adenosine in the brain by blocks adenosine reuptake (adenosine makes you drowsy)
how do benzodiazepines act on the receptors?
- bind to modulatory sites on the receptor complex
- GABAa receptor Cl– channel opens following GABA binding; Cl– enters cell and causes hyperpolarization
- if it binds at….
- BZ1: sedative-hypnotic/ anticonvulsant
- BZ2: : anxiety-relief, cognitive impairment
what causes the dependence and reinforcing affects of benzodiazepines and barbiturates?
increased mesolimbic DA release in the dopamine system
what are the adverse effects seen with benzodiazepines in older patients>
they have slower drug metabolism so confusion and reduced cognitive function may resemble senile dementia.
what other adverse effects do we see with benzodiazepines?
- Sleep disturbances (REM)
- Reduced sex drive/ performance
- Fetal benzodiazepine syndrome (birth defects, dependence, “floppy-infant syndrome”)
- Amnesia/ reduce learning ability**
what effects occur if benzodiazepines are takin with alcohol, narcotic, or barbiturates?
Synergistic drug effects: Severe CNS & respiratory depression if combined
what is the name of benzodiazepine that acts as roofies?
Rohypnol (flunitrazepam)
what is the schedule drug of rohypnol and why is it so dangerous?
schedule 4
Powerful benzodiazepine (10X the potency of Valium - diazepam)
why is it used as a date rape drug?
Often ground up and easily dissolves in liquid
Odorless, tasteless
Onset of effects ~30 minutes, last for hours longer than GHP
Effects potentiated when taken with alcohol:
blackout/ amnesia, confusion
Sedation, loss of muscle control
death
what is the metabolism of rohypnol?
Broken down in liver by CYP450 enzymes into metabolite 7-aminoflunitrazepam detectable in urine ~5 days
what is the half life of rohypnol?
20 hours
when does tolerance usually occur with BDZs?
as early as 1-2 weeks (generally not for anti-anxiety)
when can we see acute tolerance to BDZs? what type of tolerance do we see?
during a single drug administration
Limited to behavioral tolerance
(motor impairment, perceptual impairment)
when can we see chronic tolerance? what do we see with chronic use?
After Repeated administration reduces BDZ efficacy.
Unclear whether due to reduced ability to modify GABA, or changes in sensitivity of GABA receptor to GABA itself.
Anticonvulsant actions slow to develop tolerance
what type of withdrawal symptoms do we see with benzodiazepine?
- anxiety
a. psychological: panic, insomnia, depression - anxiety comes back even worse
b. physical : agitation, tremor, headache - distorted perceptions: hypersensitivity to sound, light, touch, taste, abnormal body sensation
- major incidents: fits, hallucinations, psychosis
what type of withdrawal do we see with BDZS?
Sedative-hypnotic withdrawal: tremors, cramps, delirium, possible convulsions (similar to barbiturate or alcohol withdrawal) generally seen in people who take the drug at high doses for > 1 month.
Symptoms last ~10 days
Low-dose withdrawal: seen in people taking lower doses for ~6 months
Anxiety, terror & panic, irregular heartbeat, increased blood pressure, memory impairment/ concentration issues, perceptual changes/ distorted reality, sensitivity to light, aches/pains, abnormal body sensation, insomnia, akathisia
Akathisia: a state of inner restlessness with outer movement that compels one to pace/ move for hours on end.
Feels like you are going to explode
