Anxiolytic Agents (aka Sedative - Hypnotic Agents)2

Question 1

Barbiturates: Increase in dose above that needed for hypnosis-sleep leads to state of general anesthesia - can progress to ___________, ultimately resulting in coma and death

Answer 1

depression of respiratory and vasomotor centers

Question 2

Benzodiazepines: Non-linear and less steep dose-response relationship indicates that much greater dosage increments are required to achieve CNS depression more profound than hypnosis-sleep - consistent with their ___________________

Answer 2

greater margin of safety

Question 3

The great majority of sedative-hypnotic drugs act to facilitate the action of GABA (γ-aminobutyric acid) at the ______________

Answer 3

GABAA receptor-chloride channel complex

Question 4

Both benzodiazepines and barbiturates (each at a separate binding site) indirectly increase the GABA-ergic effect to diminish

Answer 4

neuronal excitability further.

Question 5

Benzodiazepines intensify the effect of GABA, while ____________ the effect of GABA (both actions requiring presence of GABA for this effect). At high concentrations, barbiturates interact directly with the GABA receptor (presence of GABA is not required for effect).

Answer 5

barbiturates prolong

Question 6

Barbiturate action is ___________________(glutamate). With barbiturates, greater CNS depression and full surgical anesthesia can be obtained, thus they have a lower safety margin.

Answer 6

less selective and also depresses excitatory neurotransmitters

Question 7

_____________ - eszopiclone - zaleplon are non-benzodiazepines that interact with the benzodiazepine binding site as agonists. Commonly referred to as “Z”-drugs.

Answer 7

Zolpidem

Question 8

__________________ an antagonist at the benzodiazepine binding site, reverses the CNS effects of benzodiazepines

Answer 8

Flumazenil

Question 9

Benzo best in liver

Answer 9

L and O

Question 10

• Benzodiazepines in clinical use today bind to GABA-chloride channels with both α1 and α2/α5 subunits and result in both ____________

Answer 10

sleep and anxiolysis

Question 11

Anxiolysis

Answer 11

(Sedation). Described as a decrease in responsiveness to a given level of stimulation, with relief of anxiety, occurring at the lowest effective doses of these agents
Anxiolysis is usually accompanied by some impairment of psychomotor function. Behavioral disinhibition may also occur
Non-sedative anxiolytics exist (buspirone and propranolol), but most benzodiazepine antianxiety agents in use today also produce sedation

Question 12

Anticonvulsant Effects

Answer 12

Higher doses of most barbiturates and some benzodiazepines inhibit formation and spread of seizure activity in cortical neurons. Some do so at doses that do not cause severe sedation or effects on mental or motor activity (phenobarbital, clonazepam). Diazepam (or lorazepam) is drug of choice for status epilepticus. [Discussed further in separate lecture on AEDs]

Question 13

Muscle Relaxation.

Answer 13

Action to inhibit spinal cord polysynaptic reflexes may aid in muscle spasms. Effect requires high doses, thus usually accompanied by significant CNS depression.

Question 14

Hypnosis

Answer 14

All of the benzodiazepine agents will induce sleep at high enough doses

Question 15

Anesthesia

Answer 15

Short-acting barbiturates (thiopental) used to induce-maintain surgical anesthesia. Benzodiazepines are NOT capable of inducing or maintaining anesthesia but are used as adjuncts for their anxiolytic and amnesia-producing properties).

Question 16

Tolerance.

Answer 16

. A common feature when agents are used continuously in high doses. May require increase in dose to maintain effect. Metabolic and pharmacodynamic components of tolerance are seen. Occurs rapidly to sedative and anticonvulsant effects, less so to anxiolytic action.

Question 17

All benzodiazepines have similar pharmacodynamic actions so differences in their pharmacokinetic properties are

Answer 17

important factors in determining their clinical usage.

Question 18

• Oral

All benzodiazepines have similar pharmacodynamic actions

Answer 18

Rapidity of oral absorption is factor in determining utility in prn usage (situational anxiety, difficulty in falling asleep)
Diazepam, alprazolam, and triazolam have rapid oral absorption
Oxazepam and temazepam have slow oral absorption.

Question 19

All benzodiazepines have similar pharmacodynamic actions

• Intramuscular

Answer 19

This route is used when a faster onset is desired or oral access is compromised
Lorazepam has consistent and reliable intramuscular absorption
Diazepam and chlordiazepoxide have poor IM bioavailability - poor water solubility in ECF

Question 20

Barbiturates are classic inducers of _____________ and represent a major source of clinically significant drug interactions that has contributed to their declining use

Answer 20

CYP450 enzymes