Anxiolytics and hypnotics

Question 1

Describe GABA neurotransmission

Answer 1

1. glutamate -> GABA via glutamate decarboxylase
2. GABA can bind to:
   a. GABA A receptors on post synaptic cell that hyperpolarise cell
   b. GABA B receptors on pre synaptic cell that have -ve inhibition of release
3. GABA can then be re up taken by:
   a. glial cells - GABA transaminase breaks down GABA into SSA (sunninic semialdehyde)
   b. pre synaptic cell - GABA-T breaks down GABA into SSA

Question 2

How is GABA broken down?

Answer 2

GABA broken down into Succinic Semialdehyde (SSA) via GABA-T

which is broken down into Succinic Acid via SSDH

Question 3

Where is glutamate decarboxylase found

Answer 3

In the cytosol

Question 4

Where are GABA T and SSDH found

Answer 4

In the mitochondrial membrane

Question 5

What are the main proteins found in the GABA A receptor

Answer 5

• GABA R protein
• GABA modulin
• barbiturate receptor protein
• BDZ (benzodiazepine) receptor protein

Question 6

What is bicucullin

Answer 6

A GABA competitive antagonist

Question 7

What is flumazenil

Answer 7

A BDZ competitive antagonists

Question 8

What are the 6 pathways of GABA A receptor activation

Answer 8

o Pathway 1 – linkage of GABA-RP, GABA-M and BDZ-RP and opening of Cl—channel.
o Pathway 2 – initiation of pathway 1.
o Pathway 3 – increased affinity of binding of GABA/BDZ (reversible).
o Pathway 4 – linkage of Barb-RP and BDZ-RP and opening of Cl—channel.
o Pathway 5 – increased affinity of binding of GABA (NOT-reversible).
o Pathway 6 – direct activation of Cl—channel.

Question 9

What effect do barbs have on opening of binding sites

Answer 9

Increase frequency

Question 10

What effect do BZDs have on opening of binding

Answer 10

Increase duration

Question 11

Compare the GABA A receptor binding of barbs and BDZs

Answer 11

Less excitatory transmission

Barbs are MORE dangerous - more dangerous than SEs; induction of surgical anaesthesia and small therapeutic window

Question 12

What are clinical uses of BDZs and Barbs

Answer 12

Anaesthetics
Anticonvulsants
Anti-spastics
Anxiolytics (BDZs only)
Sedatives/Hypnotics (barbituates, BDZ)

Question 13

What are examples of drugs used as anxiolytics

Answer 13

Diazepam (valium), Chlordiazepoxide, Nitrazepam. (Oxazepam can be used if the patient has a hepatic impairment as liver will take longer to metabolise it)

Question 14

what are examples of drugs that are used as sedatives/hypnotics

Answer 14

Temazepam (BDZ), Oxazepam (BDZ), Amobarbital (barb) and Nitrazepam can also be used for a hypnotic effect at night followed by an anxiolytic effect during the day

Question 15

Define anxiolytics

Answer 15

remove anxiety without impairing mental or physical activity

Question 16

Define sedative

Answer 16

reduce mental and physical activity without producing a loss of consciousness

Question 17

Define hypnotic

Answer 17

Induce sleep

Question 18

What characteristics should an anxiolytic, sedative or hypnotic have?

Answer 18

Large therapautic window, not depress respiration, produce natural sleep, not interact with other drugs, not produce ‘handovers’, not produce ‘dependance’.

Question 19

What is the structure of barbiturates

Answer 19

tend to have a single ring structure with two R groups that are ethyl groups and phenyl/1-methylbutyl

Question 20

What effect do barbiturates have, give an example

Answer 20

Sedative/hypnotic effects

eg amobarbital that causes severe intractable insomnia with half life 20/25hr

Question 21

What are unwanted effects of barbiturates

Answer 21

Small therapeutic windows - depress respiration
Reduce REM sleep -> hangovers
Induce enzymes
Potentiate effects of other CNS depressants - alcohol
Tolerance and dependence becomes issues

Question 22

What is the chemical structure of benzodiazepines

Answer 22

Triple ring structure

Question 23

What do benzodiazepines act on

Answer 23

GABA A receptors (not GABA B) and there are similar potencies in different benzodiazepines but its the pharmacokinetics that differentiate use

Question 24

Pharmacokinetics of benzodiazepines

Answer 24

• Administration – orally or IV, peak plasma at ~1h.
• Binds plasma proteins strongly, high lipid solubility.
• Extensive liver metabolism.
• Excretion – urine (glucuronide conjugates).
• Duration of action – VARIES GREATLY.
  Short-acting or long-acting – slow metabolism and/or active metabolites.

Question 25

What are advantages of BDZs?

Answer 25

• wide therapeutic window - overdose just leads to a prolonged sleep
• mild effect on REM sleep
• does not induce liver enzymes

Question 26

What are unwanted effects of BDZs

Answer 26

• sedation, confusion, amnesia, ataxia -> impair manual skills
• potentiate other CNS depressants
• tolerance (less than barbs and include ‘tissues only’) and dependence (less intense than barbs)
• free plasma concentration increases when co administered with aspirin, heparin

Question 27

What is flumazenil

Answer 27

A BDZ antagonist that can reverse effect of BDZs (prolonged sleep)

Question 28

What is zopiclone

Answer 28

A ‘z drug’ that is short acting and acts on BDZ receptors (but they are not BDZs, they are cyclopyrrolones) - minimal hangover effects but dependency is a problem

Question 29

What are examples of other anxiolytics

Answer 29

Antidepressants
Antiepileptics eg tigabines
Antipsychotics eg olanzapine
Propanolol
Buspirone - 5HT1A Receptor agonist