BZD, barbiturates and buspirone Flashcards
What BZD is associated with procedural sedation and amnesia?
Midazoalm
What BZD is associated with use for muscle relaxation?
Diazepam
Which BZD is associated with use for drug and alcohol withdrawal symptoms?
Lorazepam
What BZD effects are associated with developed tolerance with chronic use?
Anti-seizure and hypnotic effects
Describe the tolerance to anti-anxiety effects of BZDs
Develops slowly or not at all
Describe the physiological dependence to BZDs; psychological?
Relatively little; more common than physiological (tendency to continue use when not needed)
What happens when someone discontinues using benzodiazepines after long-term use?
Symptom recurrence, rebound or withdrawal
Recurrence definition (BZDs)
Return of symptoms that required therapy (common with BZDs, weeks-months long)
Rebound definition (BZDs)
Symptoms are similar to before but with greater intensity (within hours or days of last dose)
T/F: Rebound symptoms are greater with long-acting BZDs than with short-acting.
False (short-acting have greater rebounds)
How is rebound intensity related to dose and duration of use (BZDs)
Proportionally
Withdrawal general symptoms (BZDs)
General anxiety, sensory disturbances, flu-like
Withdrawal autonomic sympathetic signs (BZDs)
Tachycardia/hypertension, tremors, abdominal distress, sweating
Withdrawal symptoms following abrupt DC after long-term use (BZDs)
Seizures and delirium
Explain how to discontinue BZDs
Switch to longer-acting drug (lorazepam, diazepam) and gradually taper dose by 10% per 1-2 weeks
How can BZDs, specifically longer-acting ones, suppress abstinence symptoms from other CNS depressants like alcohol and barbiturates?
Cross-dependence
Why should the use of BZDs be avoided in the elderly?
ADEs= confusion, anterograde amnesia are more common in elderly
Paradoxical ADEs of BZDs (2)
Hyperactivity, aggression (esp. in pediatric population)
BZD use in pregnancy
Chronic use is contraindicated (category D and X)
Toxicity presenting signs (BZDs)
Severe drowsiness and ataxia, vital signs usually normal
T/F: BZDs when taken orally do not cause fatal toxicity, but are potentially fatal when combined with alcohol or other CNS depressants.
True
Treatment: BZD toxicity
Supportive care (technically could use flumazenil)
Competitive antagonist at the BZD receptor sign on GABAa
Flumazenil (Romazicon)
Flumazenil blocks the effects of ____, but does NOT reverse the effects of ___(4).
BZDs and non-benzo BZD agonists; barbiturates, ethanol, general anesthetics, or opioids
Flumazenil administration, onset time, half-life
IV, 1-2 minutes, 1 hour (metabolized by liver)
2 uses of flumazenil:
Reverse sedation effect of BZDs after anesthesia, BZD overdose
T/F: Flumazenil is used to treat BZD overdose especially because it re-establishes the airway.
False- not a substitute for establishing airway-assisted ventilation
Boxed warning on flumazenil
Seizures (esp. in patients on long-term BZD therapy who have taken TCA)
ADEs= amnesia, agitation, dizziness, nausea, may precipitate withdrawal in dependency
Flumazenil (BZD receptor antagonist)
Phenobarbital and methohexital + CYP enzymes…
Strong inducers of CYP enzymes (multiple DDIs)
Onset of methohexital
Rapid (extremely lipid soluble)
What determines methohexital’s DOA after a single dose? Plasma half-life?
Redistribution; hepatic metabolism
What determines phenobarbital’s DOA? Plasma half-life?
Both determined by hepatic metabolism (less lipid soluble, so does not enter brain as rapidly)
Phenobarbital: % metabolized
75%
Phenobarbital: onset time
60 minutes
Phenobarbital: duration
10-12 h
Phenobarbital: lipid/water
3
T/F: Barbiturates have poor analgesic properties but DO relieve anxiety.
True
Main use and schedule of phenobarbital
Epileptic seizures (status epilepticus), CIV
Off-label use of phenobarbital
Treatment of alcohol and sedative/hypnotic withdrawal
Describe phenobarbital’s use as a sedative/hypnotic
No longer recommended (overdose is deadly)
Uses of methohexital (2)
- Induction of general anesthesia
- procedural sedation
Tolerance to phenobarbital’s ____ effects occurs, but NOT to its ___ or ____ effects.
Sedative-hypnotic; respiratory depression or anti-seizure
What causes the tolerance seen with phenobarbital use?
Increased metabolic clearance of the drug (CYP autoinduction)
Physical dependence on phenobarbital is a serious problem - what symptoms are seen 8-12 H after last dose?
Anxiety, tremors, restlessness, weakness, nausea, vomiting, insomnia
Physical dependence on phenobarbital is a serious problem - what symptoms are seen 2 days after last dose?
Increased sympathetic activity, delirium, seizures, death
How do you treat physical dependence to phenobarbital?
Supportive, switch to long-acting barbiturate and taper dose
T.I. Of barbiturates (phenobarbital)
10
ADEs= potentially fatal CNS/respiratory depression, hypotension, paradoxical stimulatory response (esp. in pediatrics), alkalinization of urine (enhances elimination)
Barbiturates (phenobarbital, methohexital)
MOA of busprione:
Unclear, partial agonist at 5-HT1a and 5-HT2 receptors
Does buspirone bind to any site on the GABAa receptors?
No
Use of buspirone
Generalized anxiety disorder (less effective for other anxiety disorders like social or panic)
ADEs of buspirone (4)
Dizziness, restlessness, tachycardia, palpitations (think CNS and CV)
What occurs upon abrupt discontinuation of buspirone?
Nothing- no rebound anxiety or withdrawal symptoms
Use of buspirone while pregnant
Safe during pregnancy (category B)
Use of buspirone while driving
Fine- does not affect motor skills
Does buspirone show any abuse potential?
No (not a controlled substance)
What is the main advantage of buspirone in treating anxiety?
No sedative/hypnotic or euphoric effects, NOT additive with other CNS depressants
What is the onset of buspirone?
3-4 weeks (until anti-anxiety effect becomes established)
T/F: Buspirone reverses withdrawal from other CNS depressants.
False
Buspirone anti-seizure effects
None
Buspirone muscle relaxant effects
None
Lipid solubility and ______ are directly proportional
onset of action
After a single dose, ______ of highly lipid soluble drugs i dependent on the rate of ______ out of the CNS into another compartment
duration of action
redistribution
Lipid solubility and ______ are inversely proportional
duration of action
When given chronically, duration of action is dependent on ______
hepatic elimination
How do AA and glucose readily cross the BBB?
L-amino acid transporter
GLUT1
The _____ is the primary drug target of CNS drugs
neuron
neurons are classified by what 3 things?
function
location
NT they release
Function of neurons are supported by what?
glial cells
Target selectivity in the CNS is based on what?
- different functions of the brain are mediated by release of specific NTs in discrete regions of brain by distinct groups of neurons
- specific functions of the brain can be targeted by using drugs highly selective for the receptor subtypes
Major excitatory NT
glutamate
Where does glutamate act?
AMPA, KA, NMDA ion channels
major inhibitory NT
GABA
GABA A
Cl ion channels
GABA B
GPCRs
nicotinic and muscarinic NT
acetylcholine
4 amine NTs
Serotonin
DA
NE
histamine
What NT is associated with Parkinson’s?
DA
What NT is implicated in virtually all CNS functions?
Serotonin
What NT modulates arousal and appetite?
Histamine
Where is MOA-A expressed?
GI tract
liver
CNS
1st pass metabolism of MOA-A
dietary tyramine
MAO-A inactivation of
Epi
NE
5-Ht
DA
MOA-A inhibitors are used to treat
depression
Where is MOA-B expressed?
platelets
CNS
MAO-B is selective inactivation of what?
DA
MAO-B inhibitors are used to treat
Parkinson’s
Major drug classes of CNS depressants
BZD
Barbiturates
Ethanol
General anesthetics
Decreased responsiveness to external stimuli, but not asleep; anti-anxiety effect
sedation
also referred to as dissociative anesthesia
sedation
pharmacological definition of sleep-like state from which the individual can still be aroused
Hypnosis
unresponsive to external stimuli but responsive to pain
unconsciousness
state of unconsciousness where individual is unresponsive to external stimuli or pain, is paralyzed and amnestic
anesthesia
Non-selective CNS depressants
ethanol
barbiturates
general anesthetics
Selective CNS depressants
BZDs
How do CNS depressants bind?
allosteric agonists of GABA A
5 subunits of GABA-A
2alpha
2 beta
gamma
Where is the GABA binding site?
between beta and alpha
Binding of GABA leads to what pore opening?
Cl
Where is the BZD binding site?
between alpha and gamma
alpha 1 subunit mediates what functions?
sedation
amnesia
ataxia
alpha 2,3 subunits mediates what functions?
anti-anxiety
muscle relaxing effects
alpha 5 subunits mediates what functions?
long-term memory and learning effects
Binding of BZDs locks the channel into a conformation that increases its affinity for GABA and increases the _____ of chloride channel opening
frequency
T/f BZDs will produce sedation and hypnosis given orally by themself
false
t/f barbiturates need the gamma subunit to bind
false
Barbiturates increase the ____ of chloride channel opening
duration
t/f at high doses, barbiturate binding can activate the receptor in the absence of GABA
true
