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Anxiolytic, Sedative and Hypnotic Drugs Flashcards

1
Q

Outline the GABA-ergic synapse neurochemistry

What does glutamate decarbxylase require to work

A

GABA synthesised in pre-synaptic terminal from GLUTAMATE

using

GAD (glutamate decarboxylase)- needs vitamin B6

GABA stored in vesicles in pre-synaptic terminals (loaded in by proteins in the synaptic vesicle)

Released on calcium influx

GABA diffuses across cleft to stimulate post synpaptic receptors

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2
Q

What type of molecule is GABA

A

AA… inhibitory NT

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3
Q

What tye of neurons release GABA

What is the exception

A

Short axon interneurons withi a brain region….

regulatory and inhibitory role

regulates firing rates

regional control

In the nigro-striatal pathway is dopamine

In the striato-nigral pathway this a LONG GABAergic pathway inhibiting substantia nigra

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4
Q

What receptors does GABA act on and to what effect

A

GABA-A, commonly on glutamatergic neuron (but not exclusively)

Type 1 receptor…. ion linked, ionophore. Upon binding, it chages conformation to allow Cl- in, down its concentration gradient.

Causes hyperpolarisation of post synaptic cell

Makes cell more difficult to create action potential (takes down from -60mV to like -80mV)

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5
Q

Outline the inactivation of GABA

A

GABA inactivated by reuptake into pre-synaptic terminal OR glial cells

Metabolised AFTER reupake by GABA-T (GABA transaminase) in either cell to SSA (succinyl semialdehyde)

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6
Q

Where are GABA-B receptors

A

Autoreceptors sitting on GABA presynaptic terminal, reducing GABA release and synthesis

(like a2 in the noradrenaline system)

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7
Q

Outline GABA metabolsim

A

GABA–> SUCCINIC SEMIALDEHYDE
by GABA TRANSAMINASE

SUCCINIC SEMIALDEHYDE –> SUCCINIC ACID
by SUCCINIC SEMIALDEHYDE DEHYDROGENASE (SSDH)

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8
Q

What is the end product of GABA metabolism and what happens to it

A

Succinic acid … goes back into the TCA

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9
Q

What is the TCA GABA shunt

A

a-ketoglutarate is turned into glutatmate for GABA production

And succinic acid (following the eventual break down of GABA) is put back into the TCA

5-10% of TCA in brain is used to make GABA

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10
Q

Outline the location of enzymes involved in GABA metabolism

A

GAD- produced in pre-synaptic GABA terminals (cytoplasmic), used to convert glutamate to GABA

GABA-T and SSDH- these are mitochonrial enzymes in both the glial cells and the GABA terminals

Note that GAD is exclusive to the presynaptic GABA terminal

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11
Q

What is the consequence of imhibitors of GABA metabolism

A

INHIBITORS OF GABA METABOLISM

leads to a large increase in brain GABA concentration

Enhancement of GABA released from the presynaotic terminal

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12
Q

List two examples of GABA metabolism and the effects

A

Anticonvulsants

VIGABATRIN - inhibits GABA-T

SODIUM VALPROATE - GABA-T and SSDH inhibitor

Used in the treatment of epilepsy, increase concentration of GABA in the central synapses

Sodium valproate is also thought to block VSSC which may reduce glutamate release from excitatory neurons

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13
Q

Outline the GABA-A receptor complex

A

Just GABA-A receptor NOT GABA-B

Made up of 4 main proteins:

  • GABA receptor protein
  • Benzodiazapine receptor protein
  • Barbiturate receptor protein
  • Chloride channel protein
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14
Q

What happens when GABA binds to the GABA-A receptor protein

A

Binds to GABA receptor protein part of the complex

  1. This causes conformational change which causes a linkage with the BDZ receptor protein by GABA modulin

This causes a transient opening of the chloride channel, allowing for influx of Cl- ions into the post synaptic cell. Hyperpolarisation

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15
Q

What does BDZ do at the GABA-A complex

A

Bind at the BDZ receptor protein

  1. Enhance normal action of GABA by opening chlorine channel (enhancing pathway 1) i..e the pathway in which GABA receptor protein links with the BDZ receptor protein by GABA modulin.
  2. Also increases binding of GABA to the GABA receptor protein i.e. increases the affinty of GABA receptor protein for GABA. This is then RECIPROCAL because this increased GABA binding then increases BDZ binding

These both enhance the action of GABA

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16
Q

What does barbiturates do at the GABA-A complex

A

Bind to barbiturate receptor brotein

  1. Enhance normal action of GABA (i.e enhance the way in which GABA links with the BDZ receptor protein by GABA modulin to open the chloride channel
  2. Enhance binding of GABA to the GABA receptor protein (but this is NOT reciprocal, so no increase in barbiturate binding following this )
  3. Direct action to open the chloride channel protein (at higher dosage), not the case with BDZ
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17
Q

How does bicuculline work

A

Competitve GABA receptor antagonist

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18
Q

How does flumazenil work

A

Competitive BDZ receptor antagonist (i.e. the antidote!)

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19
Q

T/F Barbitruates and BDZ can work without GABA

A

F….. they have ALLOSTERIC ACTION,

They need GABA to work

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20
Q

Mecahnism of action of BZs and BARBs

A

BZs increase FREQUENCY OF OPENINGS

BARBs increase DURATION OF OPENINGS

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21
Q

Ouline selectivity of BARBs and BZs

A

BARBs LESS SELECTIVE THAN BZs

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22
Q

What are the extra effects of BARBs other than GABA

A

Reduce EXCITATORY TRANSMISSION (some antagonistic effect of glutamate)

OTHER MEMBRANE EFFECTS (direct Cl- blocking), BDZ cannot do this

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23
Q

What do the extra effects of BARBs outside of GABA account for

A

INDUCTION OF SURGICAL ANAESTHESIA

LOW MARGIN OF SAFETY

(i.e. reducing excitatory transmission, and the cl- blocking account for this)

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24
Q

Clinical uses of BZs and BARBs

A

ANAESTHETICS (BARB only, see below)

ANTICONVULSANTS

ANTI-SPASTICS

ANXIOLYTICS

SEDATIVES / HYPNOTICS

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25
Example of anaesthetic from BZ or BARB
Thiopentone which is a BARB.... note that BDZ CANNOT INDUCE SURGICAL ANESTHAEIA SO THIS HAD TO BE A BARB!
26
Example of anticonvulsant
DIAZEPAM; CLONAZEPAM; PHENOBARBITAL | so BDZ or BARB can be anticonvulsants!
27
Example of antispastic
DIAZEPAM This has a CENTRAL action on a motor neurons coming out of the spinal cord (look at other NM blockers!)
28
Definition of anxiolytic drug
REMOVE ANXIETY WITHOUT IMPAIRING MENTAL OR PHYSICAL ACTIVITY (“MINOR TRANQUILLISERS”)
29
Define sedative drug
REDUCE MENTAL AND PHYSICAL ACITVITY WITHOUT PRODUCING LOSS OF CONSCIOUSNESS
30
Define hypnotic drug
INDUCE SLEEP
31
What uses do we use the same drugs for
Same for sedatives and hypnotics, just increase the dose This is why anxiolytics are grouped separate from sedatives and hypnotics
32
What is the ideal drug for anxiolytic etc
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
33
Structure of barbiturates
6C ring Different side chains
34
Uses of barbiturates
Sedative/hypnotic AMOBARBITAL SEVERE INTRACTABLE INSOMNIA (i.e. cannot be treated with BDZ) t½ 20-25h (also anticonvulsants, phenobarbitol and the others in the general uses list)
35
Unwanted effects of BARBs
Depress respiration--> overdosing is lethal ALTER NATURAL SLEEP (reduces REM) increases HANGOVERS/ IRRITABILITY ENZYME INDUCERS (can affect metabolism of warfarin, GCs and TCAs) POTENTIATE EFFECT OF OTHER CNS DEPRESSANTS (e.g. ALCOHOL), increasing risk of overdose TOLERANCE DEPENDENCE
36
What type of tolerance occurs ith BARBs
Tissues and pharmacokinetic tolerance
37
Outline withdrawal symptom associated with BARBs
``` INSOMNIA ANXIETY TREMOR CONVULSIONS DEATH ```
38
Structure of BDZ
Three ring structures Small changes in the side chains but these very small changes can lead to different PK, affecting duration of action
39
Differentiate flumazenil and BDZ
Very similar structure to the BDZs but no efficacy Effective BDZ antagonist
40
Where do BDZ act
Around 20 of them but all same mechanism of action ALL ACT AT GABA-A RECEPTORS
41
What determines which BDZ is used
ALL SIMILAR POTENCIES & PROFILES PHARMACOKINETICS LARGELY DETERMINE USE
42
Outline the administration of BDZ
WELL ABSORBED P.O. PEAK [PLASMA] = 1hr I.V. vs STATUS EPILEPTICUS
43
When might BDZ be administered IV
E.g diazepam STATUS EPILEPTICUS
44
Distrubution of BDZ
BIND PLASMA PROTEINS STRONGLY HIGHLY LIPID SOLUBLE WIDE DISTN
45
Outline metabolism of BDZ
USUALLY EXTENSIVE (LIVER)
46
What is the excretion of BDZ
URINE; Inactive GLUCURONIDE CONJUGATES
47
Duration of action of BDZs
Varies greatly
48
Two categories of BDZ
Short acting Long acting SLOW METABOLISM AND / OR ACTIVE METABOLITES
49
Exampes of long acting and short acting BDZs
Long acting= diazepam (32hr) short acting= temazepam, oxazepam (8hr) All converted to glucuronide for excretion
50
Why does diazepam have a longer duration of action
Diazepam has longer half life as it is more slowly metabolised Converted to short acting ones (Temazepam/oxazepam) to glucuronide and also converted to nordiazepam (60h) whcih all have BDZ activity Glucoronide
51
How are BZs used for anxiolytic and sedative/hypnotic action
Long acting for ANXIOLYTIC: - DIAZEPAM - CHLORDIAZEPOXIDE (LIBRIUM) -NITRAZEPAM ( or short acting Oxazepam) Short acting for SEDATIVE/HYPNOTICS: - Oxazepam - Temazepam (or long acting Nitrazepam)
52
Why is oxazepam used as anxiolytic despite being short acting drug
Short acting, but used in patients with hepatic impairment If hepatic impairment, then the long acting ones will be proken down to slowly, so you want to give something which breaks down faster so the effect isn't too prolonged (e.g. atracurarine instead of tubcurarine)
53
When might nitrazepam be used in sedative/hypnotic action, despite being longer acting
It is longer action so you'd think it should be used in anxiety, not insomnia. But if they have insomnia and early morning waking, or anxiety throughout the day, nitrazepam might be good to allow a more prolonged effect.
54
Advantages of BDZ
Wide margin of safety Mild effect on REM sleep DO NOT INDUCE LIVER ENZYMES
55
Why is there a wide margin of safety with BDZ
Oversose leads to ROUSABLE prolonged sleep HAVE AN ANTIDOTE=FLUMAZENIL
56
Unwanted effects of BDZ
SEDATION, CONFUSION, AMNESIA,ATAXIA (IMPAIRED MANUAL SKILLS) POTENTIATE OTHER CNS DEPRESSANTS (ALCOHOL; BARBs, antihistamines) TOLERANCE (but less than BARBs) DEPDENDENCE FREE PLASMA INCREASE BY ASPIRIN AND HEPARIN
57
What is the tolerance dependent on for BARB and BDZ
barb: tissue and PK BDZ: tissue only
58
Outline the withdrawal syndrome associated with BDZ and what we do about it
WITHDRAWAL SYNDROME SIMILAR TO BARBs (LESS INTENSE) Withdraw slowly (weeks or months)
59
Outline co-administration of BDZ with heparin, aspirin etc.
BDZ are highly plasma bound If you co-administrate with heparin or aspirin, you can get displacement of the drug from the plasma protein and this can increase the free plasma concentration of the BDZ
60
Example of a non BDZ/BARB sedative/hypnotics
Mostly drugs which have other primary uses Zopiclone
61
Example of other non BDZ/BARB anxiolytics
SOME ANTIDEPRESSANT DRUGS SOME ANTIEPILEPTC DRUGS SOME ANTIPSYCHOTIC DRUGS PROPRANOLOL BUSPIRONE
62
Duraction of zopiclone action
5hr
63
Where does zopiclone act
Acts at BZ receptors BUT NOT a BDZ
64
Class of zopiclone action
CYCLOPYRROLONE
65
Efficacy of zopiclone compared to BDZ
Similar
66
Benefit of zopiclone over BDZ
MINIMAL HANGOVER EFFECTS BUT DEPENDENCY STILL A PROBLEM
67
What antidepressant drugs can be used as anxiolytics
SSRIs
68
What is the benefit and disadvantage of SSRI for anxiolytic
LESS SEDATION & DEPENDENCE DELAYED RESPONSE in terms of antidepressant and anxiolytic LONG-TERM TREATMENT (due to reduced dependency)
69
Example of antiepileptic drugs and why improve
Valproate and tiagabine (inhibits GABA reuptake... underlies anxiolytic and anticonvulsant mechanism)
70
Give some examples of antipsychotic drugs used as anxiolytics
OLANZAPINE, QUETIAPINE
71
How can propanalol help with anxiety
Physical symptoms IMPROVES PHYSICAL SYMPTOMS TACHYCARDIA (b1) TREMOR (b2)
72
Mechanism of buspirone and advantage and disadvantage
5HT1A partial agonist Fewer side effects (less sedation and ataxia) Slow onset of action (days or week)

Pharm (33 decks)

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