Anxiolytics

Question 1

What is an anxiolytic drug?

Answer 1

A drug that is used to treat chronic anxiety (i.e. apprehension, restlessness, tension)

Question 2

What is a sedative drug?

Answer 2

A drug that decreases activity, moderates excitement and calms the patient

Question 3

What is a hypnotic drug?

Answer 3

A drug that produces drowsiness and facilitates the onset and maintenance of sleep

Question 4

What determines the range of CNS depressant drugs? (if the drug is an anxiolytic, sedative, or hypnotic)

Answer 4

The dose; the higher the dose concentration, the more severe the drug becomes (i.e. anxiolytic–>sedative–>hypnotic)

Question 5

What are the clinical uses of anxiolytics? (7)

Answer 5

(1) Reduce anxiety
(2) Induce sleep
(3) Sedation before surgery (may produce some anterograde amnesia)
(4) Epilepsy
(5) Balanced anesthesia for surgery
(6) Control of withdrawal symptoms
(7) Muscle relaxation (only if muscle tension is associated with anxiety- does not work on neuromuscular junction)

Question 6

What are the two types of CNS drugs?

Answer 6

(1) Type A: Continuous CNS depressants- well defined therapeutic index
(2) Type B: Lower therpeutic index

Question 7

What are the Type A drugs? (4+)

Answer 7

(1) Barbiturates
(2) Alcohol
(3) Chloral hydrate
(4) GHB (gamma hydroxybutyrate)
(5) other general anesthetics

Question 8

What are the Type B drugs? (1)

Answer 8

(1) Benzodiazepines

Question 9

What is the different between the therapeutic index of Barbiturates (i.e. Phenobarbital) and Benzodiazepines (i.e. Diazepam)?

Answer 9

Diazepam has a 10 fold increase in therapeutic index

Question 10

If you want to depress activity of the CNS, what is the primary inhibitory neurotransmitter in the brain? How do these receptors work?

Answer 10

GABAa receptors; they permit Cl- ions to flow through the membrane, keeping the cell’s potential negative, which makes the action potential less likely.

Question 11

T/F The Anxiolytics increase the synthesis of GABAa to make it work better.

Answer 11

FALSE; they don’t replace GABAa but make the natural GABAa work better

Question 12

How do the Axiolytics work with the GABAa receptors? How do the Benzodiazepines differ from Barbiturates in the channel?

Answer 12

When benzodiazepines or barbiturates bind to the ligand gated channels (at a different site than where the GABAa goes), the channels are more likely to open or stay open when the drugs are bound to them; Benzodiazepines only open the channels when GABAa is also bound to them while Barbituates can open the channel in absence of GABAa

Question 13

Benzodiazepines: Mechanism of Action

Answer 13

Potentiation of GABA-stimulation of GABA receptors:

(1) Does not stimulate the receptor itself. It is not an agonist.
(2) When it binds to the GABA receptor, the receptor bings to GABA with a higher affinity
(3) Therefore, they increase GABA transmission, but only through GABA that has already been released into the synapse

Question 14

<p>

| Why are Benzodiazepines safer than Barbiturates?</p>

Answer 14

<p>
(1) With Benzodiazepines you get receptor saturation at a lower concentration but do not increase its efficacy (2) With Benzodiazepines, you increase the efficacy in the brain which is unsafe</p>

Question 15

What are the classifications of Anxiolytics?

Answer 15

(1) Barbituates (less common in current practice)

(2) Principal type: Benzodiazepines

Question 16

What determines the choice of Benzodiazepines? What is the exception to this?

Answer 16

• The pharmacokinetics (this will tell you how long it’s going to be acting; i.e. different drug for sleep aid vs. anxiety)
• Alprazolam for panic disorders and agoraphobia

Question 17

Where are Benzodiazepines metabolized? What is special about where they are metabolized (what are the exceptions)?

Answer 17

• Liver
• There are ACTIVE metabolites with long half lives, over 24 hours; one drug that can turn to 3 drugs in a sequence (Lorazepam and Oxazepam are fast acting, rapidly metabolized)

Question 18

What is important about the active metabolites of Benzodiazepines? What is an exception?

Answer 18

• The half life of the molecule is not important but the half life of the effect of the molecule is important because you have to add up all the different metabolites
• Triazolam does have an active metabolite but for some reason they are readily metabolized in the liver; they have one of the shortest duration of effects

Question 19

T/F Benzodiazepines are bound up to 90% to plasma proteins therefore you have to make sure to give elderly lower dosages to combat their slowing metabolism.

Answer 19

TRUE

Question 20

What are the 5 Benzodiazepines (including short-intermediate, fast acting, peak plasma concentration, and effect half life)?

Answer 20

(1) Alprazolam (S-I), 1-2hr, 12-15hr
(2) Lorazepam (S-I) 1-6hr, 10-18hr
(3) Midazolam (S-I) IV only, 2-5hr
(4) Trizolam (S-I) 1-2hr, 1.5-5.0hr
(5) Diazepam (L) 0.5-2.0hr, 20-50hr

Question 21

T/F you do not want to treat Benzodiazepines chronically.

Answer 21

TRUE

Question 22

Benzodiazepines: Therapeutic Effects (4)

Answer 22

(1) Antianxiety: at low doses, associated with little CNS depression
(2) Sedation: suppression of responsiveness to a constant level of stimulation seen at low doses, but tolerance usually develops within days.
(3) Hypnosis: fast acting are the best, usually short acting if antianxiety action not wanted.
- latency of onset reduced, REM duration decreased, duration of slow wave reduced
- tolerance to hypnotic action observed over days/weeks; rebound increase in REM seen on withdrawal
(4) Anticonvulsants: Diazepam is used for status epilepticus and alcohol withdrawal

Question 23

Benzodiazepines: Side Effects (4)

Answer 23

(1) Respiration- depression at the medullary respiratory center is observed at higher than sedating doses (not as toxic as barbituates)
(2) Euphoria- makes fast acting, short-lived benzodiapepines particularly likely to be abused; psychological dependence common with long term use
(3) Paradoxical excitement- may be associated with “CNS disinhibition”
(4) Anterograde amnesia- inability to remember events occurring while under effects of the drug

Question 24

Benzodiazepines: Drug Interactions (4)

Answer 24

(1) Additive or even synergistic CNS depression with other sedative hypnotics and alcohol
(2) Functional cross tolerance with EtOH and other sedative hypnotics observed
(3) Oral contraceptives reduce Diazepam-elimination
(4) Asymmetric metabolic cross tolerance with EtOH and barbituates
- Benzodiazepines do not induce the liver P450 enzymes
- EtOH and Barbituates do induce the liver P450 enzymes

Question 25

What is the concept of “Asymmetric Metabolic Cross Tolerance” with Barbiturates and Benzodiazepines? (4)

Answer 25

(1) Barbituates can induce the liver enzymes that metabolize BOTH Barbiturates and Benzodiazepines
(2) If a person takes Barbiturates, over a period of time the half life of the Barbituates in that individual becomes shorter
(3) On the reverse side: Benzodiazpeines are relatively ineffective at inducing the liver enzymes
(4) If a person takes Benzodiazepines, over a period of time the half-life of those drugs in that individuals will remain the same

Question 26

What is the Benzodiazepine antagonist? What is its half life? How is it taken?

Answer 26

Flumazenil; Short half-life; I-V only

Question 27

T/F Flumazenil attaches to a different site on the GABAa receptor than Barbiturates to enable its response.

Answer 27

FALSE; it goes to the same site but it keeps the Benzodiazepines from having the effect of increasing the effects of GABAa

Question 28

What is Flumazenil used for?

Answer 28

If someone that overdoses and present with a coma, this takes away the effect of the Benzodiazepines and can help them to get out of a coma (make sure to monitor them because of the short half-life). Only takes away the Benzodiazepine component (it will not do alcohol)

Question 29

What are the actions of Barbiturates? (1)

Answer 29

(1) Sedative- Hypnotic
(2) Anticonvulsant properties
(3) Induction liver microsomal enzymes

Question 30

What are the 3 Barbiturates we need to know? What are their therapeutic uses? Which one is still used?

Answer 30

(1) Thiopental- IV anesthetic (ultra short acting)
(2) Pentobarbital- Sedatives
(3) Phenobarbital- Epilepsy
- Thiopental is still used-

Question 31

Barbiturates- Mechanism of Action

Answer 31

Potentiation of inhibitory neurotransmission, GABAa receptor
- more efficacious than Benzodiazepines

Question 32

What are other drugs that are used to treat anxiety? What do they do? (4)

Answer 32

(1) Busipirone- very slow acting, novel structure
(2) Beta-adrenergic blockers- decrease sympathetic tone
(3) Alpha-2 agonist- Clonidine
(4) Tricyclic antidepressants- panic attacks

Question 33

What are other sedatives/hypnotics? What do they do? (3)

Answer 33

(1) Zolipidem, Zaleplon- act as benzodiazepine binding site, but have unique structures
(2) Chloral hydrate- largely restricted to institutional use, inexpensive but may have significant toxicity
(3) Antihistamines: Hydroxzine, Diphenhydramine- OTC sedatives/hypnotics