Exam 4: Anxiety Pharmacokinetics Flashcards
drugs that relieve anxiety are
anxiolytic
- relieve tension, worry, stress
- produce calm relaxed state, without drowsiness!!, mental clouding, and incoordination
sedative-hypnotic drugs
CNS depressants
barbiturates, benzodiazepines, alcohol
-sleep aides/sedation - calms people down
-at high doses - CNS depressants induce coma and deah, respiratory depression
make people very tired!!!
benzodiazepines are used for what anxiety disorders
GAD, panic disorder, OCD, social phobia, alcohol withdrawal, acute situational anxiety
benzodiazepine trade name
valium, xanax
SSRIs are used for
social phobia, OCD, panic disorder, PTSD
what schedule drug are barbiturates
schedule II: pentobarbital -anesthesia
schedule III: butobarbital
schedule IV: luminal -anti-anxiety, sleep inducing aspects
high abuse and addiction liability dependent on lipid solubility
uses for barbiturates (4)
- surgical anesthesia
- sleep aid
- anti-anxiety
- anticonvulsant - used for seizures
barbiturate ROA
IV most common, also oral
short term: IV - surgical anesthesia
long-term: oral - anticonvulsant or antianxiety
intranasal common route for barbiturate abuse!
what is absorption of barbiturates dependent on
lipid solubility!
ultrashort acting have highest lipid solubility - get to brain fastest onset 10s-20min
long acting have lowest lipid solubility onset an hour to 12 hrs (ex: phenobarbital)
distribution of barbiturates
readily pass thorugh BBB and placental barriers, detectable in milk of nursing mothers
accumulation in skeletal muscle and adipose tissue (depot binding)
- these drugs do not work well in those obese bc there is lots of depot binding
- depot binding can be problem: at high levels when some gets stuck over time it leaks out into bloodstream
metabolism and excretion of barbiturates
-broken down in liver
INACTIVE metabolites excreted in urine
after chronic use what types of tolerance do you see
metabolic tolerance: cyp450 enzyme induction associated with inc drug metabolism, lower blood concentration of drug, and reduced drug effectiveness
cross tolerance: makes other drugs not work as well
pharmacodynamics of barbiturates (2)- what neurotransmitter involved
enhance GABA actions in CNS
-positive allosteric modulator: inc affinity of GABA A receptor for GABA, makes it more sensitive
they directly open Cl- ion channels in GABA A receptor without GABA present
- extreme sedation possible bc it acts as a false agonist for GABA
at higher doses what do barbiturates act as - pharmacodynamics
antagonists for AMPA and Kainate glutamate receptors
-for seizure disorders - it shuts down hyperexcitability
sedation is good in moderation- remember too high can cause respiratory depression
dangers of barbiturates: tolerance
-behavioral tolerance to some sleep-producing and anti-seizure effects of barbiturates
-respiratory depression does NOT show tolerance - reduced margin of safety due to rightward shift on curve
it does not effect the brainstem sedation - short window btw it being fun and causing respiratory depression
dangers of barbiturates - withdrawal and addiction
- they produce significant physical dependence and have high potential for abuse
- can’t quit cold turkey after chronic use, need to gradually come off to avoid rebound hyperexcitability and seizures like alcohol withdrawal
dangers in high doses of barbiturates
- poor coordination, slurred speech, life-threatening respiratory depression
- at its height of use, more than 15000 deaths/year in US were from barbiturate overdose
mild/moderate doses of barbiturates causes
nausea/vomiting/diarrhea drowsiness impaired cognition/attention/judgement slurred speech emotional dysregulation
serious doses of barbiturates effects
shock
coma
death
birth defects (prenatal exposure - crossing placental barrier)
what type of drug accounts for 2/3 of all medical prescriptions for psychoactive drugs
benzodiazepines
- 30% all anxiety disorders diagnoses treted with benzos
- over 40% of panic disorder pts prescribed benzos
what schedule drug are benzodiazepines
schedule 4 drugs
use patterns of benzodiazepines
women twice as likely to use than men
45% use or less than 30 days - short term going on aplane
80% of use is for less than 4 months
15% use is greater than 12 months
suffix of benzodiazepines
azolam or azepam
suffix for barbiturates
atol
benzodiazepine ROA
oral - most common; xanax
IV, IM (more common) injections (Ativan)
intranasal-common during abuse
absorption and distribution of benzodiazepines
BDZs have common molecular structure
onset of action determined by lipid solubility (shorter acting have higher lipid solubilities) ex: 90% xanax absorbed from GI tract
high blood albumin protein binding (depot binding!!)
-also from fat and muscle - can extend time drug can be detected in one’s system
metabolism and excretion of benzodiazepines
short acting: metabolize in one step into inactive metabolites
ex: temazepam (restoril) or lorazepam (ativan)
long acting: metabolized in many steps in liver - ACTIVE metabolites produced
ex: diazepam or flurazepam
DO NOT induce CYP450 liver enzymes
-so less risk for metabolic tolerance, still get behavioral tolerance
pharmacodynamics of benzodiazepines (what neurotransmitter)
positive allosteric modulator of GABA A receptor
- enhance GABA A activity by up to 700%
- inc sensitivity of GABA receptor to GABA, but does not open pore to Cl-
also inc actions of adenosine in the brain
- blocks adenosine reuptake
- adenosine accumulates in system for longer - opposite of caffeine
benzodiazepines on glutamate neurons
decrease glutamate release
anticonvulsant effect
benzodiazepines on NE neurons
dec NE release
improves concentration and focus
sedative effect
benzodiazepines on serotonin neurons
dec 5-HT release
antianxiety effect
therapeutic uses of benzodiazepines
anxiety - short term relief of severe anxiety
anticonvulsant
sleep (reduces insomnia)
muscle relaxant
presurgical anesthesia - patient conscious but less aware - wisdom teeth
adverse effects pf benzodiazepines - after chronic use
in older people with slower drug metabolism: confusion and reduced cognitive function resemble dementia
- sleep disturbances in REM
- dec sex drive/performance
- tolerance (44% long term users), usually behavioral tolerance, occurs as early as 1-2wks - not for anti-nxiety
- fetal BNZ syndrome (birth defects, dependence, floppy infant syndrome)
- amnesia/reduced learning ability!!! - in moment you focus but nothing sticks
- severe CNS and resp depression if combined with alcohol, narcotics, barbiturates
mesolimbic dopamine changes-BDZ
- dependence and reinforcing aspects of BDZ and barbiturates due to inc mesolimbic DA release
- BDZ binds to GABA A receptor turning GABA off, disinhibiting so DA turned on and VTA releases DA to NaCC
Rohypnol
BDZ
- “roofies”
- 10x potency of valium (diazepam)
- effective dose = 2mg
- ground up and dissolved in liquids (clear, odorless)
- onset of effects 30 min and lasts for hours
effects of rohypnol when taken with alcohol
severe blackouts sedation loss of muscle control confusion complete memory loss death
acute tolerance to BDZ
single drug administration
-limited to behavioral tolerance
-motor impairment, perceptual impairment
when blood concentration inc you have more impairments they dec as blood concentration dec
chronic tolerance and BNZ
could be due to pharmacodynamic tolerance
- repeated administration dec BDZ efficacy
- unlear if this is due to reduced ability to modify GABA or changes insensitivity of GABA receptor to GABA
- anticonvulsant actions slow to develop tolerance !!! - good
list some psychological withdrawal symptoms of BDZ
-anxiety panic attacks intrusive thoughts insomnia depression phobias
list some physical effects of BDZ withdrwal symptoms
agitation tremor nausea palpitations tingling, numbness
bc disinhibiting sympathetic NS
distorted perceptions of BDZ withdrawal symptoms
hypersensitivity to sound, light, touch, taste
abnormal body sensation (itching, pain, stiffness)
feeling self or world to be abnormal
major incidents of BDZ withdrawal
-whenhigh doses stopped abruptly
delirium
hallucinations
psychosis
fits
2 forms of abstinence syndrome, less severe than barbiturate withdrawal symptoms
sedative-hypnotic withdrawal
low-dose withdrawal
sedative-hypnotic withdrawal
tremors, cramps, delirium, possible convulsions
seen in ppl who take the drug at high doses for > 1 month
symptoms last ~10 days
low-dose withdrawal
seen in people taking lowr doses for longer period of time (6 months)
anxiety, terror, panic, irregular heart beat, inc BP, memory impairment, concentration issues, senstive to light, insomnia, AKATHISIA
akathisia
state of inner restlessness with outer movement that compels one to pace/move for hours on end
-feel like you are going to explode
-cannot sit still
enhanced insula activation! - notice slight changes in body and freak
treatment of BDZ withdrawal
detox with tapering drug concentration over an 8-12 wk period
flumazenil: BDZ receptor antagonist can be used to treat BDZ overdoses
what drug class would you prescribe to a patient with insomnia?
benzodiazepine bc it has a not as steep curve which means more wiggle room to adjust dose without worrying about inducing a coma
higher therapeutic inde than barbiturates - less risk for respiratory depression
example of a second generation anxiolytic
buspirone (BuSpar)
Buspirone (BuSpar)
-partial agonist for 5-HT1A receptor - raphe mediated to reduce anxiety
does NOT directly act on GABA system, non-sedative
-more effective at reducing cognitive aspects of worry/poor concentration than the physical symptoms of anxiety
-effective for GAD, less effective for OCD
Buspirone effects
onset is quite long and its effectiveness is much less than BDZs
-less useful for those who take the drig only when needed for situational anxiety
short haf life so dosing must occur twice a day
advantages of buspirone (5)
- treats depression that often accompanies anxiety
- anxiety reduction is not accompanied by sedation, confusion, or mental clouding
- does not enhance CNS depressant effects of alcohol or other CNS depressants (no respiratory depression)
- little/no potential for recreational use or dependence
- no withdrawal syndrome reported
SSRIs
antidepressants used to treat anxiety
take 4-6 wks to become effective where BDZs act immediately
-early on may worsen anxiety
can relieve both anxiety and depression
reduces OCD symptoms unlike buspirone
tricyclic antidepressants
combination drugs
block SERT, NET, weakly DAT
monoamine oxidase inhibitors
these are the first choice because they have fewer side effects, a higher therapeutic index, and low abuse potential
SSRIs
anxiolytics and LC
BDZ enhance inhibitory function of GABA
reduced LC firing - anxiolytic effects
serotonin reuptake blockade by SSRIs reduces LC firing also
tricyclic antidepressants (desipramine) and MAOIs enhance NE function which inhibits firing of LC neurons by acting on the a2 autoreceptors
