Antianxiety Agents

Question 1

Which drugs act on the GABA receptor?

Answer 1

Barbiturates

Benzos

Question 2

Name a barbiturate

Answer 2

phenoBARBital

Question 3

Name a benzodiazipine

Answer 3

diazepam, triazolam, alprazolam, clonazepam,
midazolam

Question 4

Name a benzodiazipine receptor agonist

Answer 4

zolpidem, eszopiclone

Question 5

Name a benzo receptor antagonist

Answer 5

flumazenil

Question 6

Name a Melatonin congener

Answer 6

ramalteon

Question 7

Name a 5-HT1a (minor, α1, α2, D2) receptor agonist
**Non-sedative Anxiolytic: **

Answer 7

buspirone

Question 8

Compare a sedative with a hypnotic

Answer 8

Sedative: drug causing a calming effect;
tranquilizer

Hypnotic: sleep-inducing or promoting drug

Question 9

As dose increases, can produce sleep (=“hypnosis”), anesthesia, coma and death. When do you get anxiolytic & sedative effects?

Answer 9

Low doses

Question 10

True/false: Benzodiazepines require proportionately **much higher **doses to produce anesthesia, coma or death—only do so in combination w/ other sedatives.

Answer 10

TRUE

much “safer”

Question 11

True/false: Antidepressants are the drug of choice for panic disorder. (also agoraphobia)

Answer 11

True

SSRIs most common; others also effective but have more adverse effects.

**Alprazolam effective but can cause rebound anxiety when discontinued; risk of dependence.

Question 12

Social phobia** can be treated with **clonazepam

Answer 12

ALSO behavioral therapy*; also SSRIs, other
ADDs; Beta blockers used to suppress tremors and shaking.

*TOC for specific phobias

Question 13

What is the principle treatment for generalized anxiety disorders?

Answer 13

principal treatment is benzodiazepines; also buspirone; some ADDs.

Question 14

Which drug has the following MOA:

bind to sites on GABA receptor
• enhance duration of GABA-mediated chloride flux
• cause **hyperpolarization of neuron = **neuronal inhibition
• at higher concentrations, directly open GABA Cl- channel
• Suppress glutamate transmission via AMPA receptors
• Direct membrane effects to inhibit neurons

Answer 14

Barbiturates and older sedatives

Question 15

What are three main concerns with barbiturates?

Answer 15

Relatively low therapeutic index—dangerous in overdose
• High incidence of dependence and addiction
• Barbiturates induce CYP enzymes

Question 16

What are two current uses of barbiturates?

Answer 16

For anesthesia; anesthetic induction: thiopental

For seizure disorders: phenobarbital

Question 17

Which drug has the following MOA?

• *bind to sites on GABA receptor
• EFFECT:to facilitate GABA mediated Cl- influx**
• cause hyperpolarization of neuron = neuronal inhibition

Answer 17

Benzodiazipines

Differences from barbiturates:

• NO DIRECT EFFECT: Can’t directly open channel (no effect w/o presence of GABA)—this limits their toxicity!
• Only one binding site per receptor
• Don’t act on all subtypes of GABA receptors

Question 18

How do full benzo agonists work?

Answer 18

(e.g. diazepam, alprazolam, zolpidem,
etc.): bind to BZ receptor, enhance GABA channel opening, Cl- influx

*Hypnotics like zolpidem selective for BZ receptors on α1 subunit

Question 19

How does a benzo antagonist work?

Answer 19

_ (flumazenil)_ – competitively binds to BZ
receptor but does not change GABA effects
• No effects when given alone
• Will competitively inhibit effects of both full agonists (BZs), hypnotics like zolpidem, and inverse agonists

Question 20

What are some systemic effects of benzos?

Answer 20

Sedation

* higher doses cause cognitive impairment (anterograde amnesia)
- “Disinhibition”
• Amnesia (useful for anesthetic use)

Question 21

What are the main respiratory effects of benzos?

Answer 21

Significant respiratory depression w/ pulmonary disease; also in children
Contraindicated (as are all sedatives) w/ o_bstructive sleep apnea_

Question 22

True/false: you can develop tolerance with benzos.

Answer 22

TRUE

Symptoms: anxiety, insomnia, irritability, CNS excitability, seizures

Question 23

What are the levels of dependence in benzos and barbiturates?

Answer 23

• Barbiturates have high risk—schedule II
• BZs: much lower but still some risk of
  psychological dependence; schedule III or IV

Question 24

How do the benzos differ in kinetics?

Answer 24

Rate of entry into CNS: more lipophilic enter CNS faster
• Fast entry useful for anesthesia (midazolam)
• Others entering faster: alprazolam & diazepam
Rapid absorption and rapid CNS entry associated w/
higher abuse liability (esp. alprazolam & diazepam)

Question 25

Compare the duration of action of benzos

Answer 25

• Most **long-acting** (t1/2 ≥ 12-24 hrs) ***_diazepam, clonazepam_*** • Medium duration (t1/2 6-12 hrs): ***_alprazolam_*** • Short duration (t1/2 \< 6 hrs): **_triazolam, midazolam_**

Question 26

How does flumazenil work?

Answer 26

* *_• Reverses most effects of BZs_** * Useful in BZ overdose, & to hasten recovery after use in surgery* • Rapid acting but short duration (30-60 min) – **must give repeated doses to reverse OD (i.v. only)** • Does **_NOT_** work against *alcohol or barbiturates*

Question 27

How does buspirone work?

Answer 27

**_No sedative, hypnotic, anti-seizure or euphoric effects_** - Partial agonist at *CNS 5-HT1a receptors* • Not useful for acute anxiety; ***efficacy requires 1+ weeks***

Question 28

What is the major advantage of buspirone?

Answer 28

ADVANTAGES: ***no tolerance, dependence or abuse liability***

Question 29

How is Ramelteon used?

Answer 29

* *Synthetic agonist acting at MT1 & MT2 melatonin receptors;** * no activity at GABA receptors* - FDA-approved for **long-term use for insomnia**

Question 30

Which benzos are used as sleep aids?

Answer 30

Benzodiazepine Receptor Agonists (BRAs) • Zolpidem, zaleplon, eszopiclone (“Z” drugs) *All suppress REM and deep sleep* **Guidelines suggest limiting BZ use for up to 3 weeks**

Question 31

How do the BRAs work?

Answer 31

Bind to a subset of GABA receptors: those w/ **_α1 subunit_** • Effects reversed by **flumazenil** • **_NO_** anxiolytic, anticonvulsant or muscle relaxing activity

Question 32

What are the major safety announcements with zolpidem?

Answer 32

- known risk of next-morning impairment - should not drive or engage in other activities that require complete mental alertness January 2013 Drug Safety Communication: The recommended initial dose of certain immediate-release zolpidem products (Ambien and Edluar) is **5 mg for women and either 5 mg or 10 mg for men**.