Final: Anxiolytics Flashcards
What are the differences between GABAA and GABA-B Receptors?
GABA-A: Axodendritic/somal Ionotropic Postsynpatic inhibition Cl- influx IPSP (hyperpolarization) decrease AP target of depressants
GABA-B:
AxoAXONAL, metabotropic, presynaptic. Decrase Ca2+ influx, decrease transmitter release. GHB is example, so if Baclofen.
What 3 factors affect the onset/duration of barbiturates?
- lipid solubility
- Plasma protein binding
- rate of excretion
How do you synthesize barbiturate
Malonic acid (apple ester) + Urea (urine) –> Barbituric Acid –> Barbiturate
Short acting Barbiturates
1) Thiopental = anesthetic
Rapid enter, slow to leave. Why? Lipid soluble. Cross BBB to get in fast, then absorbed in fat.
2) Methohexital
Intermediate-to-short acting barbiturates
These are the ones getting abused 1) Secobarbitals (red) 2) Pentobarbital (yellow) 3) Amobarbital (blue) (SPA, or RYB)
*Use: Anesthesia, hypnosis, anti-anxiety
Long-acting barbiturates
1) phenobarbital (Luminal)- lasts 10-12 hours
2) Therapeutically useful in epilepsy
*Use: seizures, sedation
Are barbiturates GABA agonists/antagonists?
NO!
Are barbiturates GABA agonists/antagonists? If not, then wtf is going on?
NO! They are neither!
They bind to increase receptor affinity for GABA.
Barbiturate Mechanisms of Action
1) Increases affinity of GABA-A receptor
2) facilitates coupling of GABA-A receptor to Cl- channel.
3) Opens Cl- Channel directly
More: Block AMPA, bind to various ionotropic receptors [N], in high doses
*Barbiturate Mechanisms of Action
1) Increases affinity of GABA-A receptor
2) facilitates coupling of GABA-A receptor to Cl- channel.
3) Opens Cl- Channel directly
More: Block AMPA, bind to various ionotropic receptors [N], in high doses
GABA-A receptors
Alpha Subunit
Beta Subunit
Gamma Subunit
Where are the barbiturates?
1) Alpha- picrotoxin?, ethanol
2) Beta- neurosteroids, barbiturates, GABA
3) Gamma- Benzodiazepines
Barbiturates site near middle of channels, can open ion channel on their own
What is a GABA agonist?
Muscimol
Allosteric regulation of GABA binding to Gaba-A receptor by depressants
1) depressant increases affinity of gaba for receptor
2) Allosteric effect
3) Binding of regulatory site that is not active site changes shape of active site
Benzodiazepines:
1) Admin
2) Absorption
3) Action
4) Distribution
5) biotransformation
1) Admin- oral, apenteral
2) WEAK BASE, GI Tract
3) 6-24 hr. depends onrate, biotranformation, ppb
4) Cross BBB
5) Converted by lier to active/inactive metabolites
*What 3 factors affect onset/duration of BENZODIAZEPINe action?
1) BIOTRANSFORMATION
2) ppb
3) rate of excretion
Short Acting Benzodiazepines
1) *Alprazolam (Xanax)
2) Triazolam (halcion)
Intermediate-acting BENZ
Clonazepam (Clonopin)
*Iorazepam (Ativan)
Long-Acting BENZ
Diazepam (valium) (20-100 hr.)
Chlordiazepoxide (libruim) (50-100 hr; chlorazepate)
The idea behind short acting benzodiazepines is that they make better tolerance, so less addictive. Problem?
More dependence
Long Acting Benzodiazepines biotransformation
Phase 1 –> Active metabolism,
Phase 2–> BDZ + UDP-O-carbon conjugation to inactive metabolite for excretion
Short Acting Benzodiazepines biotransformation
Phase 2–> BDZ + UDP-O-carbon conjugation to inactive metabolite for excretion
*Benzodiazipine mechanisms of action
1) Increase affinity for GABA-A receptor for GABA
2) Couple GABA-A to Cl- channel
BUT: need GABA in system to work
*Benzodiazepines and Barbituates: Which is more potent?
Barbiturates are more potent
Benzoiazepine increases the ____ of Cl- channel opening
FREQUENCY
Barbituates increase the ___ of Cl- channel opening.
DURATION
Picotoxin
Blocks Cl- Channel
Can cause seizures and act as stimulant
Once neurosterioids bind, they are converted to
allopregnanolone
GABA + BDZ
increase CL- Influx
enhances inhibition of NS
GABA + BDZ + BDZ blocker
normal
GABA + BDZ + GABA blocker
barely any influx
GABA
hyperpolarization
GABA + Diazepam
increased magnitude of hyperpolarization
BDZ agonists
Midazolam
Clonazeplam
Flunitrazepam
Diazepam
BDZ competitive antagonist
Flumazenil
Beta-Carboline inverse agonists
DMCM, Beta-CCM, beta-CCE
Acute effects of BDZ and Barbituates
Mock ADHD: decrease arousal/altert, decrease anxiety, disinhibition, decrease concentration
DrunK: sedation, mild euphoria, intoxication, hypnosis, impaired memory, suppress REM, decreased activity impaired motor
Barbituates vs. BDZ, which like alcohol in terms of intoxication
Barbituates
TOXIC effects of barbiturates and BZD
Suppressed respiration
stupor
Coma
Barbiturates: death, unlikely for BDZ unless combined with other depressants
Barbiturate OD
no safe antidote
Therapy, vital monitoring, respiratory assistance,
activated charcoal to prevent GI absorption, increasing renal pH NOT recommended
What are APPROVED therapeutic uses of BARBITURATES?
Anesthesia - short term (thiopental)
Anti-Seizure (phenobarbital)
What are APPROVED therapeutic uses of BARBITURATES?
Anesthesia (thiopental)
Anti-Seizure (phenobarbital)
UNAPPROVED therapeutic uses of BARBITURATES?
Anti-anxiety (secobarbital)
hyponosis (amobarbital)
Non-Benzodiazepines Hyponosis
Ambien (Zolpidem), Lunesta (Eszopiclone), and Sonata (Zalepion)
Selective for BZ1 subtype link to sleep, selective for hypnotic effect
Report induce sleep, no hangover, fewer side effect, less likely to induce dependence
Non-Benzodiazepines Hyponosis
Ambien (Zolpidem), Lunesta (Eszopiclone), and Sonata (Zalepion)
Selective for BZ1 subtype link to sleep, selective for hypnotic effect
Report induce sleep, no hangover, fewer side effect, less likely to induce dependence
Cellular tolerance of Barbiturates/BDZ
Decrease GABA receptors
Metabolic tolerance of Barbiturates/BDZ
Increases metabolism
Behavioral tolerance of Barbiturates/BDZ
Functioning in presence of drug
Cross tolerance
across depressants
Tolerance of barbituates reduces…
Therapeutic index, bring desired effect dangerously close to toxic effect
BDZ dependence
mild, but discomforting
NOT life threatening
Anxiety, irritability, sweating, vertigo, insomnia, cramps, sensitivity, tachycardia
positive reinforcement: weak reinforcer
Abuse model of BDZ
patients with history of drug abuse more likely to escalate dosage and abuse
Therapeutic model
patients use recommended doses, many no escalate and under medicate
Non barbiturate depressants
Gamm hydoxy… (GHB)
Flunitrazepam (Rohypnol)
Methaqualone (Quaalude)
All not marketed in US
GHB
Not barbiturate
Powerful depressant
Structure similar to GABA
Liquid Ecstasy, Liquid X or E, Soap
Disinhibition, drunkenness, amnesia
Acute overdose (stupor, coma)
Predatory Drug
Rohypnol- memory blocking
Powerful benzodiazepine
Not marketed in U.S.
Roofies, Roachies, Rope, Ruffies
Potent long-acting amnesic
Predatory drug
Psychological Symptoms of Anxiety
Apprehension, worry, nervousness, agitation
Physical Symptoms
increase bp, heart rate, erratic respiration rate, decreased salivary flow, GI disturbance, muscle tension
Barbiturate risks
Acute toxicity
lethal od
varying rate of tolerance
physical/psychological dependence
BDZ risks
OD when combined with other drugs (opiods)
prolong physical dependence
Psychological dependence if susceptible
How do you treat BDZ dependence?
Tapering dosage over time, replace with longer acting DBZ, initiate psychotherapy
Buspirone (Buspar)
Partial 5HT1A agonist
no tolerance/dependence
no rebound anxiety upon termination
Weak side effect: sedation, memory, motor
no interaction with other depressants
But: action requires several weeks, and less effective as treatment
SSRIs
Most popular treatment of anxiety and depression
inhibit reuptake of 5-HT primarily
fewer risks compared to depressants
Fewer side effects than TCAs or MAOIs
Vilazodone (Viibryd)
Partial agonist at 5HT1A receptors
selective serotonin reuptake inhibitor
Amygdala hypothesis of anxiety
Sensory input via thalamus
Lateral N. of Amygdala
Center/Basolateral N. of amygdala
(Output is CRH)
Stria terminalis
Projection to CNS/ANS
Cortical Releasing hormone (CRH)
41 amino acid peptide
Hormone regulating ACTH release from anterior pituitary, which induces cortisol release from adrenal cortex
Neurotransmitter released in anxiety circuits
LC neurons: BDZ
enhances inhibitory function of GABA on LC
LC neurons: SSRIS
reuptake block of 5-HT enhances 5-HT inhibition of LC
LC Neurons: CRH
has anxiety producing excitatory effect on LC
DREADD Experiment
Designer receptors exclusively activated by designer drugs
HM3/HM4 dye
1) inject virus in brain
2) CNO ligand in water, binds to receptor
hM4Di- inhibition
hM3Dq= excitation
LC neurons activated by stress
More time in open field maze
Fear vs. anxiety
Anxiety- apprehension about possible future events
Fear- emotional response to clear and current danger
BENZO agonist
increase GABAA affinity, helps GABA work, increase attraction, allows more Cl- into neurons, more inhibition
BENZO antagonist
binds to the same sight of benzodiazepine, block benzodiazepine BUT The problem is, the only drug used is one antagonist and some get seizure from that.
BENZO inverse agonists
increase anxiety
reduction in Cl- influx
Angiogenic: produce anxiety. Experiment only.
Bind to BENZO site
