2.17: Sedatives Flashcards
(71 cards)
1
Q
What are the clinical uses of sedative hypnotics?
A
- Insomnia
- Anxiety
- Alcohol withdrawal
- Anticonvulsants
- Adjust to anesthesia
2
Q
What is the effect of sedative hypnotics dependant on?
A
- Dose dependent leading to increased awareness and arousability
3
Q
How do the benzos differ from older sedative hypnotics?
A
Their effect tapers off as doses increase leading to them being less likely to cause coma or death
4
Q
Which sedative hypnotics target GABA-a receptors?
A
- Benzos
- Non benzo agonists:
- Barbiturates
- Ethanol
5
Q
Characteristics of GABA-a receptors?
A
- Ionotropic receptors
- Activation by gaba leads to increased Cl channel opening
- This causes inhibitory postsynaptic potentials decreasing neuronal firing
6
Q
Which receptor do sedative hypnotics target?
A
Only GABA-a
7
Q
Characteristics of GABA-b receptors? Where are the found? What are their effects in each location?
A
“Metabotropic G protein linked receptors”
- Presynaptic regulating release of:
a. GABA from GABAergic neurons: “homoreceptors”
b. Other NTs: “heteroreceptors” - Post synaptic:
a. Receptor activation produces membrane hyperpolarization
8
Q
Common GABA-a receptor subtype composition?
A
- 2 alpha subunits: determines receptor subtype and ability to be modulated by respected drugs
- 2 beta subunits
- 1 gamma subunit
9
Q
What can BZ1 subtype GABA-a receptors bind?
A
- Benzodiazepines
- Imidazopyridines
- Pyrrolopyrazines
- Flumazenil: agonist
10
Q
What can BZ2 subtype GABA-a receptors bind?
A
- Benzodiazepines
2. Flumazenil: agonist
11
Q
Which are the BZ1 selective drugs?
A
- Imidazopyridines
2. Pyrrolopyrazines
12
Q
Characteristics of the alpha / beta interface?
A
- 2 sites on each receptor
- GABA binds here
13
Q
Characteristics of the alpha / gamma interface?
A
- 1 site per receptor
- GABA is necessary for binding of:
1. Benzodiazepines
2. Imidazopyridines
3. Pyrrolopyrazines
14
Q
What drug is a GABA-a agonist?
A
Flumazenil
15
Q
Which categories of drugs modulate GABA-a at site other than BZ1/2?
A
- Barbiturates
- Ethanol
- Neuroactive steroids
16
Q
How do benzos work?
A
- Bind BZ1/2 sites on GABA-a receptors: 90%
- Are positive allosteric modulators of GABA-a function
- GABA must be bound four opening of Cl channel
17
Q
How do non-benzo agonists work?
A
- Bind BZ1 sites on GABA-a receptors: 60%
- Are positive allosteric modulators of GABA-a function
- GABA must be bound four opening of Cl channel
18
Q
Which are the Pyrrolopyrazines?
A
- Eszopiclone
19
Q
Which are the Imidazopyridines?
A
- Zolpidem
2. Zaleplon
20
Q
What is the mechanism for positive allosteric modulation of BZ1/2?
A
- Binding of benzo increases receptor affinity for GABA
- Increases the frequency of Cl channel opening
- Leads to inhibitory postsynaptic potential and decreased neuron firing
21
Q
How do the inverse agonists work?
A
- GABAs presence is necessary
- Negative allosteric modulators of GABA receptor function
- Decrease Cl channel opening increasing neuron firing
- Lead to anxiety, seizure, or blockage of benzo effects
22
Q
What are the Inverse agonists?
A
- Beta carbolines
23
Q
How does Flumazenil work?
A
- On its own has no effect
- Will block effect of drugs with affinity for BZ1/2
- Will NOT antagonize GABA agonists, barbiturates or alcohol
24
Q
Clinical indication for flumazenil?
A
- Benzo OD
2. Reverse Benzo sedation after surgical procedure
25
Characteristics of barbiturate effects on GABA-a receptors?
- Bind sites distinct from BZ sites
- No specificity for certain type of GABA-a receptor
- Increase DURATION of Cl channel opening
- Presence of GABA is necessary
- Cause opening of Cl channel in absence of GABA at high dose
26
Difference in the impact Benzos and barbiturates have on GABA-a receptor?
Benzos: increase frequency of opening
Barbs: increase duration of Cl channel opening
27
What potentiates impact of barbiturates?
Ethanol
28
Characteristics of neuroactive steroid effects on GABA-a receptors?
- Bind sites distinct from BZ sites, also on receptors w/o BZ
- Facilitate or attenuate GABAergic transmission depending on structure
29
Ethanol's impact on GABA receptors?
Effects similar to benzos:
1. Sedation
2. Anxiolytic
3. CNS depression
4. Potentiation of other GABA drugs
30
What do the benzodiazepines usually end in?
```
"Am," "Lam," or "Pam"
Exceptions:
1. Chlordiazepoxide
2. Clorazepate
***Their metabolite is: desmethyldiazePAM
```
31
Common uses of the benzos?
1. Anxiety
2. Sleep disorder
3. Anticonvulsants
4. ETHO withdrawal
32
Benzons or barbiturates safer?
Benzos
33
When can benzos be dangerous
1. Underlying pulmonary illness
| 2. Taking other CNS medications
34
Which benzos are lipid soluble?
All of them to varying extents
35
Protein binding of benzos?
Highly protein bound
36
Metabolism of benzos? What is the exception to this?
Most under to the following 2 steps:
Phase I: Microsomal oxidation by CYP 3A4 and 2C19
Phase II: Conjugation
****3 go directly to the second step: "LOT"
1. Lorazepam
2. Oxazepam
3. Temazepam
37
Which benzos preferred in elderly and those with hepatic function?
"LOT"
1. Lorazepam
2. Oxazepam
3. Temazepam
- Bypass phase I metabolism and have short half lives so easier on the liver
38
What is the concept of drug accumulation?
- Drugs with longer half lives, will build up [] in the system as they are taking over time risking toxicity
39
What is the impact of age on drug half life?
Drug half live will usually increase with age as liver function decreases
40
Side effects of benzos?
1. Drowsiness
2. Ataxia
3. Amnesia: good for surgical procedures
4. Rage (rare)
41
Which benzo is used as date rape drug?
Flunitrazepam / rohypnol
42
Which effects of benzos can you develop tolerance to?
- Can become tolerant to the sedative effects
| - Cannot become tolerant to the anxiolytic effects
43
What are symptoms of benzo withdrawal?
1. Anxiety
2. Insomnia
3. Confusion / delirium
* **Only seen in chronic use at high dose
44
What to do when taking patient off benzo?
- Taper dose by
45
How is 1/2 life related to tolerance and dependance?
Lower 1/2 life, higher risk of dependence
46
How is of time to onset of effects related to dependence?
Quicker time to onset, higher risk of dependence
47
How is potency related to tolerance and dependance?
Greater potency, greater risk of addiction
48
How is dose related to dependency?
Larger dose needed, greater risk of dependence
49
How is length drug take related to dependency?
Greater length, greater risk
50
Which are the BZ1 selective non-benzos drugs?
1. Zolpidem
2. Zaleplon
3. Eszopiclone
51
MOA of the BZ1 specific non-benzos?
- Positive modulators of GABA-a receptor function
52
Risk of dependence for BZ1 specific non-benzos?
- Lower than benzos
53
OD of BZ1 specific non-benzos?
- NO dangerous CNS depression UNLESS in taken in combo with other CNS depressants
54
What can be given in OD of BZ1 specific non-benzos?
Flumazenil will block effect at BZ1
55
Unique side effects of BZ1 specific non-benzos?
1. Rebound insomnia
2. Anterograde amnesia
3. Sleep Driving
4. Sleep eating
56
Which BZ1 specific non-benzos has longest 1/2 life?
Eszopiclone - 6 hrs.
57
Metabolism of BZ1 specific non-benzos?
Phase I and II in liver
58
What is a benefit of teh BZ1 specific non-benzos over benzos?
Shorter half lives give them give them less morning hangover effect
59
Which BZ1 specific non-benzos has no impact on stages of Sleep?
Eszopiclone
| ***Also has longest half life of the group
60
Which are the barbituates? Are they long or short acting?
All end in "AL"
1. Phenobarbital: Long acting
2. Methohexital: Short acting
3. Thiopental: Short acting
61
MOA of the barbituates?
1. Bind at site other than BZ1/2 on GABA-a receptor: likely lipophilic beta sub unit
2. Not specific for GABA-a subtypes as it is not binding BZs
62
Impact of barbituates at high and low dose?
LOW: increased duration of Cl channel opening in presence of GABA
HIGH: directly activate Cl channel, independent of GABA
***Low therapeutic index: lethal dose
63
Indication for short acting barbituates?
Induction of anesthesia
64
Indication for long acting barbituates?
Treatment of epilepsy
65
Side effects of barbituates?
1. Respiratory depressant: potentiated by alcohol
2. Dependence
3. Withdrawal: can be deadly
66
What should not be taken with barbiturates?
Alcohol
67
Benzos or barbs have more dangerous CNS effects?
Barbiturates
68
Impact of barbituates on the liver?
Inducers of P450 which metabolize the drug leading to a larger dose being needed to achieve same impact
69
MOA of Ramelteon?
- Melatonin agonist
- Selectively binds to MT1/2 melatonin receptors;
* *Higher affinity than melatonin
- No affinity for BZ receptors
70
Kinetics of Ramelteon?
- Moderate protein binding
- Large Vd
- Extensive first pass metabolism via CYP
- Short half life
71
Major benefit of Ramelteon?
No physical dependance of abuse potential
