Anxiolytics, Sedatives and Hypnotics

Question 1

Briefly outline the metabolism of GABA

Answer 1

GABA is produced from Glutamate via Gluatmate Dehydrogenase. Has a postynspatic receptor which results in chloride influx, as well as presynaptic autorecpetors which provide a negative ffedback effect. GABA is uptkaen from the synpase via GAT (GABA transporter) back into the presynpatic terminal as well glial cells.Then GABA-transanimase converts it to Succinic Semialdehyde, then Succinic Acid Dehydrogenase converts it to Succininc Acid. These are mitochondrial enzymes

Question 2

Name 2 inhibitors of GABA-T

Answer 2

Sodium valproate (valproic acid) an vigabatrin

Question 3

Describe the GABAa recpetor complex

Answer 3

4 proteins- a GABA receptor protein, a GABA modulin protein, a benzodiazepam receptor protein and a barbiturate receptor protein. These surround a chloride channel protein. Binding of GABA and barbs (at high conc) can directly enhance opening of the chloride channel. Binding of barbs also enhances receptro affinity for GABA. Binding of BDZs does not have a direct effect but also enhances affinity of the receptor to GABA, recpirocally in this case. This is called allosteric modulation.

Question 4

Name a GABA receptor antagonist

Answer 4

Bicuculline

Question 5

What is flumazenil?

Answer 5

A BDZ receptor anatagonist.

Question 6

How does the MOA of barbs differ from BDZs?

Answer 6

BARBs increase duration of Cl channel opening, BDZs increase frequency. BARBs are also less selective than BDZs- they also inhibits excitatory transmission and have other membrane effects. This lowers their margin of safety and gives BARBs anaesthetic properties.

Question 7

Name 5 uses of BDZs/BARBs

Answer 7

Anxiolytics, sedatives, anaesthetics (BARBs), anticonvulsants and antispastics.

Question 8

What does an anxiolytic do?

Answer 8

Remove anxiety without impairing mental or physical activity.

Question 9

What do sedatives do?

Answer 9

Reduce mental and physical ability without impairing consciousness.

Question 10

Name 6 ideal properties of anxiolytics and sedatives

Answer 10

Wide margin of safety, do not depress respiration, natural sleep, no hangovers, no drug interactions, no dependence.

Question 11

Name a sedative barbiturate and what it is used for?

Answer 11

Amobarbital, for severe intractable insomnia. Half-life 20-25 hours.

Question 12

Name 6 unwanted effects of barbiturtes

Answer 12

1) LOW SAFETY MARGINS (depress resp) 2) INDUCE OTHER ENZYMES (specifically liver microsomal ones) 3) not natural sleep, less REM, hangover, 4) tolerance induced (both receptors and enzymes play a part) 5) withdrawl- insomnia, tremors, death and 6) potentiate effects of other CNS depressors.

Question 13

Describe the structure or BARBs and name 3 examples.

Answer 13

6 emmebered carbn ring, differ by R1 and R2 groups. Examples include amobarbital common use hypnotic phenobarbitone and thiopentone.

Question 14

Name an unrelated drug that could be used as a hynotic

Answer 14

Chloral hydrate, metabolsied to trichloroethanol.

Question 15

Describe the pharmacokinetics of BDZs

Answer 15

ADMIN: Oral, can be V for status epileptics, peak plasma 1hr. DISTRIBUTION: BDZs are HIGHLY PP BOUND and highly LIPID SOLUBLE- very wide distribution. MET: liver EXCRETION glucornoide conjuagtes in the liver.

Question 16

What determines choice of BDZ

Answer 16

Their pharamcokinetics- they have varying half lives depending on speed of metabolsim (highly lipid soluble and PP bound) as well as presence of active metabolites.

Question 17

Describe the structure of BDZs

Answer 17

They have 3 rings, one of which is 7 membered. Fluzenil (a BDZ receptor antgonist) has the same but the rings are share a common boundary.

Question 18

What is the half life of a) Diazepam 2) Temazepam and 3) Oxazepam

Answer 18

1) Diazepam is 32 hours (long acting) so tends to be used as an anxiolytic 2) Temazepam and 3) Oxaezepam are 8 hrs (short acting) so tend to be used as sedatives or hypnotics.

Question 19

Can you name a short-acting BDZ that is occassionally used as an anxiolytic?

Answer 19

Oxazepam- 8hrs- hepatic impairement

Question 20

Can you name a long acting BDZ that is sometimes used as an anxiolytic?

Answer 20

Ntrazepam- 28 hrs- given just before bed for daytime anxiolytic effect.

Question 21

Why are BDZs better than BARBs?

Answer 21

1) Wider margin of sfaety- do NOT depress respiration, just cause prolonged sleep AND reversible with Flumazenil. 2) Less impact on REM sleep. 3) Do NOT INDUCE LIVER ENZYMES.

Question 22

Name 5 problems with BDZs

Answer 22

1) Potentiate other CNS depressents (same) 2) SEDATION 3) Tolerance (same but less) 4) Dependence (same but less) 5) Compete with other PP dugs like aspirin and heparin- coadministration increases bioavailibity.

Question 23

What is zopiclone?

Answer 23

A new SHORT ACTING SEDATIVE, similar to BDZs. Class: Cyclopyrrolone, half life 5 hrs. Causes a minimal hangover but problems with DEPENDENCY

Question 24

Name 5 other options for anxiolytics outside of BARBs and BDZs

Answer 24

Antidepressants eg. SSRIs, Antiepileptics e.g. Valproate (GABA T i), Antipsychotics e.e. Olazepine although marked side effects, Propranolol for tachy and tremor and Busipirone- 5HTa agonist, slow onset of days/weeks