PDA II Exam II Sharma 1.0
What are anxiolytics
Sedatives
What kind of effect do they have
Calming effect
What effect does hypnotics have
Drowsiness
Encourage the onset/ maintenance of sleep
What kind of NT is GABA
Inhibitory
Neurons that secrete GABA are called
GABAnergic
How is GABA synthesized
Via the decarboxylation of Glutamate
What enzyme catalyzes this rxn
GAD
GAD activity require what cofactor
Pyridoxal Phosphate PLP
PLP is generated from what vitamin
B6
PLP requires what for activation
Zinc
Deficiency of zinc of defect in PLP can cause
Seizures
What kind of rec are GABAA rec
Ligated-gated Cl- ion channels
What kinds to GABAA rec
GABA
BZs
Barbiturates
What is a GABAB agonist
Baclofen
The major isoform of the GABAA rec has what subunits
(2) a1
(2) b2
(1) y2
Where are the (2) binding site for GABA located
Between a1 and b2
Where are the binding sites for BZs located
Between a1 and y2
Where is the binding site for Barbiturates located
On a1
a1 subunits mediate
Sedation
Amnesia
Ataxic
a2 and a3 subunits mediate
BZ anxiolytic action
Muscle Relaxation
a5 subunits mediate
BZ Memory impairment
What effect do BZs have on GABA rec
Increase synaptic inhibition
What does this do
Enhances hyperpolarization
How do BZ enhance GABAergic rec without directly activating the GABAA rec
Increase the frequency of Cl- channel openings
Enhance Cl- conductance
What are GABAA BZ site agonists
All BZs
What are GABAA agonists
Zolpidem
Zaleplon
Eszopiclone
What is their function
Enhance membrane hyperpolarization similar to BZs
What do they no do
Cause:
Anxiolytic effect
Muscle relaxant effect
Amnesia effect
What are BZ antagonists
Flumazenil
What is the function of Flumazenil
Block BZ action
Block Zolpidem, Zaleplon, Eszopilone action
What doesn't Flumazenil block
Barbiturates
Meprobamate
Ethanol
What are the inverse agonists
B-carboline
What is the function of the inverse agonists
Blocks BZ
What does it cause
Anxiety
Seizures
Graded dose-dependent depression of the CNS is seen with
BZs
Barbiturates
Ethanol
Newer agents
Older sedatives/ hypnotics such barbiturates have a
Linear dose relationship
What does this mean
As the dose increases CNS depression increases
What is the MOA of barbiturates on GABAA
Enhances membrane hyperpolarization
How does this occur
Increasing the duration that the GABA-gated Cl- channels are opened
Describe the selectivity of Barbiturates
Less selective than BZs
Describe the absorption properties of BZs and Barbs
Lipophilic
Barbs and BZs are rapidly absorbed through which ROA
Oral
What are the rapidly absorbed BZs
Diazepam
Clorazepate
What kind of drug is Clorazepate
Prodrug
What is its active form
Desmethyldiazepam
What is the significance of Lorazepam
...
Explain the distribution properties
Rapid onset
What barrier do all sedative-hypnotics cross
BBB and Placental barrier
What happens when this occurs
Depression of neonatal vita functions
What enzyme aids BZ metabolism
CYP3A4
In what phase
Phase 1
What is phase 2
Conjugation
What are factors that affect biodisposition
In geriatric patients elimination half life is prolonged
What is dose dependent anterograde amnesia
Inability to recall events that occurred during the drugs duration of action
When does this occur
During sedation
What side effects are associated with the frequent use of BZs
Rebound REM sleep
What drug causes this
Triazolam and drugs with short duration of action
Do newer drugs affect rebound REM
No
Rebound insomnia occurs when what drugs at high doses
Zolpidem
Zaleplon
Drugs when very short half lives for hypnotic effects may lead to
Withdrawal symptoms between doses
What is Flumazenil
A BZ competitive inhibitor with high affinity
What is its use
Reversing CNS depression effects of BZ OD
Help recovery in anesthetic and diagnostic procedures
Explain the onset and DOA for Flumazenil
Rapid onset and short half life
What is its half life
0.7- 1.3 hours
What are adverse effects of Flumazenil
Agitation
Confusion
Dizziness
Nausea
What are agents that do not act through GABA-BZ mechanisms
Ramelteon
Buspirone
What rec do they act on
Melatonin (MT1 and MT2)
Explain the ROA and DOA
Rapidly absorbed via oral
Extensive first-pass metabolism (2-5 hours)
What biotransformation enzymes are involved
CYP1A2 (main)
CYP2C9
What drug reduces the plasma levels of Ramelteon and its active metabolites
Rifampin
Is Ramelteon a controlled substance
No
What rec does Buspirone not interact with
BZ sites and GABAA rec
They are partial agonists on which rec
5-TH 1A
What are their function
Inhibit the firing rate of 5-TH containing neurons
Where does this take place
Dorsal Raphe
What are the overall effects
5-TH, NE, DA
5-TH is suppressed
NE and DA are enhanced
What is the major petabolite
1-(2-Pyrimidyl)-piperazine (1-PP)
Explain the absorption of Buspirone
Rapid via oral
How long does it take for it to be eliminated
Half life is 2-4 hours
What does rifampin do to Buspirone
Decreases its half life
What is the function of rifmapin
CYP450 inducer