ANXIOLYTICS, SEDATIVES AND HYPNOTICS

Question 1

Describe CENTRAL GABA-MEDIATED INHIBITION

Answer 1

• short axon GABA interneurones in the brain –> has regulatory role
• keep firing rates within certain parameters

Question 2

Glutamate = precursor for GAB
GLU –> converted to GABA (via GAD)
- GABA = stored in vesicle in presynaptic terminal
-

Answer 2

-

Question 3

Describe the synthesis of GABA

Answer 3

Glutamate = precursor for GAB 
GLU --> converted to GABA (via GAD)
- GABA = stored in vesicle in presynaptic terminal 
- until depolarization occurs 
- VGCC opens 
- Causes exocytosis 

• chloride flows into post synaptic cell –> causes hyperpolarisation

Question 4

Describe the metabolism of GABA

Answer 4

1. GABA = converted to –> Succinic semialdehyde (SSDH)
   - via GABA- Transaminase
2. SSDH = converted to –> Succinic Acid
   - via succinic semialdehyde dehydrogenase

Succinic Acid - goes back o TCA Cycle

NOTE:
GABA-T + SSDH = Mitochondrial enzymes
- Inhibitors of GABA Metabolism leads to large accumulation of Brain GABA

Anticonvulsive drugs:

• SODIUM VALPROATE (EPILIM)
• -> SSDH + GABA T inhibitor
• VIGABATRIN (SABRIL)

Question 5

Describe the reuptake of GABA

Answer 5

• primary inactivation method of GABA
• uptake into glial cells / presynaptic cells
• GABA –> converted to SSA (Via GABA-T)

Question 6

describe the structure of the GABAa receptor complex

Answer 6

• GABA receptor protein
• Barbiturate receptor protein
• BDZ receptor protein
• chloride channel protein

GABAA receptor complex: (post-synaptic) 4 main proteins (not inc. modulin)

• GABA binds GABA receptor protein à links w/ BDZ receptor protein mediated by GABA modulin à opens Cl- channel proteins
• If BDZ binds BDZ receptor protein à enhances GABA action on Cl- channel

o Also, binding/affinity of GABA is enhanced

o This is reciprocal: binding of GABA enhances affinity of BDZ too

• BARB enhances GABA action at Cl- channel + GABA affinity (not reciprocal)

o At high doses, BARBs directly stimulate Cl- channel

• Triangle = Bicuculline is competitive GABAA receptor antagonist
• Rectangle = Flumazenil is competitive BDZ antagonist

Question 7

how do Bz + Barbs similar / differ

Answer 7

SIMILARITY:
- No activity alone b/c work by enhancing GABA (allosteric action

DIFFERENCE:

• -> Different binding sites + mechanisms:
• BZs increase frequency of openings (same duration)
• BARBs increase duration of openings (no frequency change)

–> BARBs = less selective than BZs
o Cause decreased excitatory transmission
o Other membrane effects e.g. at high doses

o May explain why:

• BARBs can induce surgical anaesthesia (BZs can’t do this)
• BARBS have low margin of safety

Question 8

What are some clinical uses of BZs + BARBS ?

Answer 8

ANAESTHETICS (BARBs ONLY : THIOPENTONE)

ANTICONVULSANTS (DIAZEPAM; CLONAZEPAM; PHENOBARBITAL)

ANTI-SPASTICS (DIAZEPAM)

ANXIOLYTICS

SEDATIVES / HYPNOTICS

Question 9

define anxiolytics

Answer 9

anxiolytics : REMOVE ANXIETY WITHOUT IMPAIRING MENTAL OR PHYSICAL ACTIVITY

Question 10

Define sedatives

Answer 10

SEDATIVES: REDUCE MENTAL AND PHYSICAL ACITVITY WITHOUT PRODUCING LOSS OF CONSCIOUSNESS

Question 11

Define Hypnotics

Answer 11

HYPNOTICS: INDUCE SLEEP

Question 12

BZ + BARBS clinically

IDEALLY: THEY SHOULD:

i) HAVE wide / narrow MARGIN OF SAFETY
ii) depress / not depress RESPIRATION
iii) produce/ do not produce NATURAL SLEEP (HYPNOTICS)
iv) interacts / doest interact WITH OTHER DRUGS
v) produces / doesn’t produce ‘HANGOVERS’
vi) produces / doesn’t produce DEPENDENCE

Answer 12

• IDEALLY: THEY SHOULD:
  i) HAVE WIDE MARGIN OF SAFETY
  ii) NOT DEPRESS RESPIRATION
  iii) PRODUCE NATURAL SLEEP (HYPNOTICS)
  iv) NOT INTERACT WITH OTHER DRUGS
  v) NOT PRODUCE ‘HANGOVERS’
  vi) NOT PRODUCE DEPENDENCE

Question 13

What are clinical uses of barbiturates?

what is half life of barbiturates

Answer 13

• sedative / hypnotic
• -> Amobarbital
• -> severe intractable insomnia
• -> Half life = 20 - 25hrs

Question 14

What are unwanted effects of barbiturates?

Answer 14

• DEPRESS RESPIRATION
• OVERDOSING = LETHAL
• alters natural sleep (decreases REM) –> Hangovers / Irritability
• potentiates effects of other CNS Depressants e.g alcohol
• enzyme inducers
• tolerance development
• withdrawal syndrome (insomnia, anxiety, tremor, convulsions, death)

Question 15

Describe the pharmacokinetics of Benzodiazepines

Answer 15

• PEAK [PLASMA] ~ 1h
• binds to plasma proteins strongly
• highly lipid soluble
• metabolized extensively in liver
• excreted via urine (glucuronide conjugates)

Question 16

Benzodiazepines –> ALL act at GABAa receptors

Answer 16

-

Question 17

What are the 2 types of

Answer 17

SHORT-ACTING
e.g temazepam, oxazepam

LONG-ACTING
–> tends to have slower METABOLISM
+ ACTIVE METABOLITES
e.g diazepam , nor diazepam

Question 18

Longer acting benzodiazepines are usually used as =

Answer 18

ANXIOLYTICS

Question 19

Short acting benzodiazepines are suavely used as =

Answer 19

SEDATIVE / HYPNOTICS

Question 20

What are advantages of Bezodiazepines?

Answer 20

• WIDE MARGIN OF SAFETY
  OVERDOSE –> PROLONGED SLEEP (but ROUSABLE)
  -IV FLUMAZENIL –> treats BZ overdose
• MILD EFFECT ON REM SLEEP
• DO NOT INDUCE LIVER ENZYMES

Question 21

What are unwanted effects of benzodiazepines?

Answer 21

SEDATION, CONFUSION, AMNESIA,ATAXIA (IMPAIRED MANUAL SKILLS)

POTENTIATE OTHER CNS DEPRESSANTS (ALCOHOL; BARBs)

TOLERANCE (LESS THAN BARBs; ‘TISSUE’ ONLY)

DEPENDENCE:

• WITHDRAWAL SYNDROME SIMILAR TO BARBs (LESS INTENSE)
• -> WITHDRAW SLOWLY
• FREE [PLASMA] increases BY e.g. ASPIRIN, HEPARIN

Question 22

what are some other drugs used as sedatives / hypnotics ?

Answer 22

ZOPICLONE

• ->SHORT ACTING (t½ ~ 5h)
• -> ACTS AT BZ RECEPTORS (CYCLOPYRROLONE)
• ->SIMILAR EFFICACY TO BZs
• -> MINIMAL HANGOVER EFFECTS BUT DEPENDENCY STILL A PROBLEM

Question 23

what are some other drugs used as anxiolytics?

Answer 23

• some anti depressant drugs
  SSRIs (see PT 16; Dr Croucher)
  LESS SEDATION & DEPENDENCE / DELAYED
  RESPONSE / LONG-TERM TREATMENT
• some anti epileptic drugs
  e. g valproate, tiagabine
• some antipsychotic drugs
  e. g. OLANZAPINE, QUETIAPINE
• Propranolol
• -> IMPROVES PHYSICAL SYMPTOMS
• TACHYCARDIA (b1)
• TREMOR (b2)
• Buspirone
• 5HT1A AGONIST
• FEWER SIDE-EFFECTS (< SEDATION)
• SLOW ONSET OF ACTION (DAYS / WEEKS)

Question 24

Benzodiazepines are used to treat ‘panic attacks’ and other anxiety states. By what mechanism do they produce their anti-anxiety effects?

A: Inhibition of GABA breakdown
B: Activation of 5HT1A receptors
C: Enhancement of the action of GABA at GABA-A receptors
D: Inhibition of GABA reuptake
E: Enhancement of the action of GABA at GABA-B receptors

Answer 24

C: Enhancement of the action of GABA at GABA-A receptors

Question 25

Which of the following drugs is commonly used in the treatment of insomnia? ``` A: Thiopental B: Phenytoin C: Baclofen D: Sodium valproate E: Temazepam ```

Answer 25

E: Temazepam