Sedatives

Question 1

Why do BZDs only increase Cl- frequency of GABA receptor?

Answer 1

BZDs bind the alpha and gama subunit of the GABA A receptor mediated by GABA ligand. MOA is dependent on GABA ligand which is why they act on channel frequency. Without GABA, BZDs do not work.

Question 2

Do BZDs activate and open GABA channel alone?

Answer 2

No. BZDs are indirect agonists of the GABA A receptor. MOA is dependent on GABA. BZDs are dependent on the GABA ligand effect.

Question 3

Why do barbiturates prolong Cl- duration of GABA receptor?

Answer 3

Barbiturates directly bind the alpha and beta subunits of the GABA A receptor mediated by GABA ligand. They are not dependent on GABA ligand (the binding sites are different than the GABA binding site).

Question 4

Do barbiturates open the GABA channel alone?

Answer 4

Yes. Barbiturates are direct agonists of the GABA A receptor.

Question 5

Is barbiturate or BZD riskier / more dangerous?

Answer 5

Barbituates. Benzodiazepines reach a plateaus in CNS depression, but barbiturates and ethanol do not (linear slope). At very high doses, barbituates may depress respiratory and vasomotor centers in the medulla, leading to coma and death.

Question 6

Which three BZDs have not active metabolites and why are they safe to use in elderly and patients with lived damage?

Answer 6

Lorazepam, Oxazepam, and Temazepam do not have an active metabolite. They are directly conjugated by UDP-glucoronasyl transferase (glucuronidation) and then directly excreted by the kidney. Because there is no active metabolite accumulation, these 3 are safe to use in the elderly and patients with liver damage (i.e. chronic alcoholism, hepatitis)

Question 7

Which two BZDs treat alcohol withdrawal symptom and why?

Answer 7

Chlordiazepoxide and diazepam due to long T1/2

Question 8

What are the symptoms of hypnotics withdrawal?

Answer 8

Increased anxiety, insomnia, and CNS excitability that may progress to convulsions

Question 9

Which drugs treat hypnotics withdrawal?

Answer 9

Clonidine for Sx only. Long T1/2 BZDs and barbiturates for underlying effect. BZDs: lorazepam-intermediate but no active metabolite, diazepam, and chlordiazepoxide. Barbiturate: phenobarbital

Question 10

Which BZD drugs easily cause daytime drowsiness and fall (ataxia) esp. in elderly and why?

Answer 10

Clorazepate, Flurazepam, Clorazepate, and Diazepam because they have a long half life (up to 100h) and therefore accumulate active metabolites.

Question 11

What is the antidote for BZDs and Zolpidem, zaleplon, eszopiclone?

Answer 11

Flumazenil

Question 12

Zoldidem, zaleplon, and eszopiclone do not cause anterograde amnesia. Why?

Answer 12

The gamma subunit of the GABA A receptoris responsible for anterograde amnesia. These drugs interact only with the alpha 1 subunit (do not interact with gamma).

Question 13

Do barbiturates cause anterograde amnesia?

Answer 13

No

Question 14

Which BZD is use in acute panic?

Answer 14

Alprazolam

Question 15

Buspirone works on which receptor to treat anxiety?

Answer 15

Buspirone is a partial agonist of the 5HT 1A receptor.

Question 16

Does buspirone cause sedation, muscle relaxant, and dependence? How long does buspirone take to onset of effect?

Answer 16

Relieves anxiety without sedative, hypnotic, or euphoric effects. No anticonvulsant or muscle relaxant properties. No dependence, rebound anxiety or withdrawal signs on abrupt discontinuance. Takes 1 to 2 weeks for effects.

Question 17

BZDs decrease what in sleeping pattern?

Answer 17

Decrease latency of falling sleep (time to fall asleep)
Increase stage 2
Decrease stage 4 (good quality of sleep)
Decrease REM (dreams)

Question 18

Why ZZESZ are more prefer to treat insomnia?

Answer 18

Because they do not cause anterograde amnesia, tolerance, or withdrawal symptoms so there is less abuse.

Question 19

Does tolerance cross BZDs, barbiturate, and alcohol?

Answer 19

Partial cross-tolerance occurs between BZDs and ethanol and barbiturates. Because partial, can sometimes switch to another if one not working.

Question 20

Are BZDs safe to use together with other CNS depressants?

Answer 20

No because they have an addictive effect of sedation.

Question 21

Why are barbiturates contraindicated in porphyria?

Answer 21

Because barbiturate increase aminolevulinic acid synthetase (CYP450 inducer) in the mitochondria, which is the enzyme that catalyzes the rate-determining step in the porphyrin biosynthetic pathway.

Question 22

What is MOA of ramelteon?

Answer 22

Ramelteon is a melatonin receptor agonist.

Question 23

Do you need to taper off the dose after 2 weeks of use of hypnotics and why or why not?

Answer 23

Yes because can have rebound insomnia and repound nightmares if do not.

Question 24

What CNS skeletal muscle relaxant is an agonist of the GABA B receptor?

Answer 24

Baclofen

Question 25

What is the biotransformation and PK of most BZDs?

Answer 25

Most benzodiazepines undergo microsomal oxidation (phase I reactions via CYP450) forming active metabolites. Benzodiazepines or active metabolites with long half-lives are predictably more likely to cause cumulative effects with multiple doses.

Question 26

Which two BZDs are likely to cause withdrawal symptoms and why? What do you do to avoid these symptoms?

Answer 26

Triazolam and Midazolam because the have short onset and short duration effects (up tp 3 h). Have to give more frequently in order to avoid.

Question 27

Which BZDs are usually used before surgery (pre-operation sedation)?

Answer 27

Triazolam and Midazolam

Question 28

Which BZDs have a short duration of action and therefore increased risk of dependence and withdrawal?

Answer 28

Alprazolam, triazolam, and oxazepam

Question 29

Phenobarbital (weak acid pKa=7.4) is excreted unchanged (20-30%) in urine and its elimination can be increased significantly by _____?

Answer 29

Alkalizing urine with sodium bicarb or acetazolamide.

Question 30

For BZDs, the development of tolerance has been associated with _____?

Answer 30

Down-regulation of brain BZD receptors