Anxiolytics and Hypnotics

Question 1

Alprazolam

Answer 1

• benzodiazepine, used to treat anxiety
• Also used to treat panic disorders
• Short duration
• Causes forebrain depression and dependence

Question 2

Buspirone

Answer 2

• Used to treat generalized anxiety disorder
• 5-HT1A partial agonist–inhibits adenylate cyclase and opens K channel.
• Also binds to dopamine receptors
• Delayed onset; therapeutic effects take 1-2 weeks to occur
• Causes little sedation and no dependence

Question 3

Clonazepam

Answer 3

• Benzo, used to treat anxiety

- Also used to treat acute manic episodes

Question 4

Chlordiazepoxide

Answer 4

• Benzo, used to treat anxiety

- Also used to treat alcohol withdrawal

Question 5

Diazepam

Answer 5

• Benzo, used to treat anxiety
• Also used as sedative and muscle relaxant (reduces spasticity by working on spinal cord; used with muscle spasm of almost any origin)
• Long duration but fast onset due to lipid solubility–rapid absorption and entry into the brain
• Causes broad CNS depression and dependence

Question 6

Flumazenil

Answer 6

• BDZ receptor antagonist

- Antagonizes zolpidem

Question 7

Lorazepam

Answer 7

• Benzo, used to treat anxiety
• Also used as hypnotic
• Less lipophilic than diazepam; absorption and onset are slower, but longer duration of action after single dose

Question 8

Baclofen

Answer 8

• GAGA-mimetic working at GABA B receptors–>hyperpolarization–>presynaptic inhibition.
• Decreased release of excitatory transmitters like glutamate
• At least as effective of diazepam in reducing spasticity, but produces less sedation.

Question 9

Tizanidine

Answer 9

• Alpha-2-adrenergic agonist that is related to clonidine. May enhance both presynaptic and postsynaptic inhibition.
• Similar to diazepam and baclofen in relieving muscle spasm.
• Side effects: drowsiness, hypotension, dry mouth, asthenia
• Interacts with cipro and fluvoxamine.

Question 10

Chloral hydrate

Answer 10

-Barbiturate. See slides

Question 11

Eszopiclone

Answer 11

• Hypnotic
• Interacts with GABA-receptor complex at binding domains close to/coupled to the BDZ receptor
• Can be used for 6 mo
• Low likelihood of dependence and W/D

Question 12

Flurazepam

Answer 12

• Benzo used as hypnotic

- Rapid onset of action, long duration of action

Question 13

Pentobarbital

Answer 13

-Barbiturate. See slides

Question 14

Ramelteon

Answer 14

• Melatonin MT1 and MT2 receptor-agonist
• Specifically indicated for treatment of insomnia characterized by difficulty falling asleep; not a controlled substance.

Question 15

Triazolam

Answer 15

• Benzo used as hypnotic

- Rapid onset of action and ultrashort duration of action

Question 16

Zaleplon

Answer 16

• Non-Benzo, used as hypnotic
• Bind BDZ receptor on GABA receptor complex
• Also work as weak anxiolytics, muscle relaxants, and anticonvulsant at hypnotic dose
• Preserve stage 3/4 sleep; minor effects on REM
• Faster onset of action than zolpidem

Question 17

Zolpidem

Answer 17

• Non-Benzo, used as hypnotic (Ambien)
• Bind BDZ receptor on GABA receptor complex
• Also work as weak anxiolytics, muscle relaxants, and anticonvulsant at hypnotic dose
• Preserve stage 3/4 sleep; minor effects on REM
• Duration of action: 5-6 hours (7-8 with sustained release). Used as oral spray for sleep initiation and sublingual tablet for middle of the night waking.

Question 18

GABA

Answer 18

• Localization: substantia nigra, globus pallidus, hippocampus, limbic system/amygdala, hypothalamus, spinal cord.
• GABA A receptor is associated with a chloride ion channel, which when activated increases intracellular chloride and hyperpolarizes neuron.
• GABA B receptor is not associated with chloride ion channel (?)
• Benzodiazepine receptor is part of GABA/BDZ receptor/Cl channel complex. Binding site is associated with alpha subunit and enhances action of GABA (make GABA better, but still need GABA).

Question 19

Benzodiazepine receptor

Answer 19

• agonists: clinically useful benzodiazepines (diazepam and zolpidem) and related hypnotics
• antagonists: block action of benzodiazepines at the receptor (flumazenil)
• inverse agonists: block action of benzodiazepines and can be anxiogenic.

Question 20

Common CNS Effects of Benzodiazepines

Answer 20

• Decrease anxiety
• Sedation
• Hypnosis
• Muscle Relaxation
• Anterograde amnesia
• Anticonvulsant action
• Minimal CN/respiratory actions at therapeutic doses

Question 21

Additive CNS depression possible with…

Answer 21

• Ethanol
• Other sedative hypnotics
• Sedating antihistamines

Question 22

Clinical uses of Benzodiazepines

Answer 22

• Anxiety states
• Sleep disorders
• Muscle relaxant (diazepam)
• Seizure treatment
• IV sedation and anesthesia
• Alcohol withdrawal (chlordiazepoxide)
• Acute manic episodes (clonazepam)

Question 23

Benzos used to treat Anxiety

Answer 23

Diazepam
Chlordiazepoxide
Alprazolam
Lorazepam
Clonazepam

Question 24

Benzo withdrawal

Answer 24

• anxiety
• insomnia
• irritability
• headache
• hyperacusis
• hallucinations
• seizures

Avoid with gradual dose reduction and switch to longer acting drugs

Question 25

SSRIs/SNRIs

Answer 25

-Used to treat panic attacks and GAD

Question 26

Beta blockers

Answer 26

-Used to treat performance anxiety

Question 27

Effects of Benzos as hypnotics for insomnia on sleep and adverse effects

Answer 27

- Decrease latency to sleep - Increase stage 1 and 2 sleep - Decrease stage 3/4 and REM sleep - Rebound insomnia upon withdrawal Related effects: - Daytime sedation - Ataxia - Tolerance and dependence - Occasional idiosyncratic excitement and stimulation - Increased death rate??