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Pharmacology and therapeutics > Anxiolytics and hypnotics > Flashcards

Anxiolytics and hypnotics Flashcards

1
Q

What do these drugs target to give them their anxiolytic and hypnotic properties

A

They enhance GABA transmission.

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2
Q

What are the two main classes of GABA receptor and where are they found

A

GABAa and GABAb
Found on the post-synaptic membrane to mediate the effects of GABA
They are ion-channel receptors (but GABAb is metabotropic-GPCR)

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3
Q

Which other drug classes can have anxiolytic and sedative effects

A

Anti-depressants
Anti-psychotics
Anti-convulsants

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4
Q

What type of amino acid is GABA

A

Neutral

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5
Q

Why is GABA called GABA

A

Gamma amino butyric acid

This is because the amino group is on the gamma carbon of GABA

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6
Q

Describe the distribution of GABA neurones

A 
Cerebral cortex 
Cerebellum 
Hippocampus 
Corpus striatum 
Hypothalamus 
Dorsal horn of spinal cord 
Relatively little in the PN
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7
Q

Describe the morphology of GABA neurones

A

They are generally short inhibitory interneurons

They inhibit the activity of localised regions (e.g they may inhibits hyperexcitabilty of the hippocampus)

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8
Q

Where can you find longer GABA tracts

A

Striato-nigral (descending version of nigro-striatal- begins in corpus striatum and ends in substantia nigra- regulating activity of dopaminergic neurones in the substantia nigra - this is a GABAergic tract
Cerebellar

Substantia nigra in the midbrain- ascending pathway to corpus striatum (bilateral pathway)- utilises dopamine- degeneration in Parkinson’s

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9
Q

Summarise the functions of GABA neurones in terms of CNS activity

A

Emotional control
Motor control
Extrapyramidal activity
Endocrine function

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10
Q

Describe the synthesis of GABA in the pre-synaptic terminal of a GABAergic neurone

A

Glutamate à GABA via GAD (Glutamate Decarboxylase).
This enzyme is exclusive to GABA nerve terminals – it is a marker for GABA neurones
Alpha-oxoglutarate (product of the Krebs Cycle) gives rise to glutamate.
The GABA synthesised is then stored in synaptic vesicles.

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11
Q

Describe the release of GABA into the synapse

A

AP arrives- Ca2+ mediated exocytosis of vesicles containing GABA

  1. GABA can bind to:
    a. GABAAR on the postsynaptic cell à hyperpolarise cell.
    b. GABABR on pre-synaptic cell à -ve inhibition of release. - functions like the alpha 2 receptor to control release of NA

GABAa= post-synaptic Cl- ionophore receptor

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12
Q

Describe the reuptake of GABA from the synaptic cleft

A

Re-uptake by Glial Cells (astrocytes) and pre-synaptic cell
GAT1- pre-synaptic cell
GAT3- glial cell

a. Glial cells – GABA-Transaminase breaks down GABA into SSA (Sunninic Semialdehyde).
b. Pre-synaptic cell – GABA-T breaks down GABA into SSA.

Or they can be simply stored in synaptic vesicles for future use.

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13
Q

Describe the metabolism of GABA after re-uptake into the synaptic cell or glial cell

A

Initially by GABA-T (GABA transaminase) to succinic semialdehyde
Succinic semialdehyde is broken down by succinic semialdehyde dehydrogenase (SSDH) to succinate
Succinate then enters the Krebs’ cycle

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14
Q

What does GABA reuptake depend on

A

Sodium dependent

Energy dependent

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15
Q

Describe the GABA shunt

A

8-10% of demand of TCA- shows how important GABA is
Alpha-oxoglutarate- leaves TCA to make glutamate to synthesise GABA
GABA broken down to succinate- which re-enters TCA
GABA that leaves TCA enters again

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16
Q

Where are the enzymes involved in GABA synthesis and metabolism located

A

GAD- cytosol

GABA-T and SSDH- mitochondrial membrane

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17
Q

What is a consequence of inhibiting the enzymes of GABA metabolism

A

An increase in the amount of GABA available in the brain.

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18
Q

Name two drugs that interfere with GABA metabolism and can be used as anti-covalents

A 
Sodium valproate (acts on GABA-T and SSDH (but more so on SSDH)) - also blocks VGSC (Epilim). 
Vigabatrin (selective GABA-T inhibitor )- covalently binds to GABA-T (Sabril)- suicide inhibitor
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19
Q

Describe the different subunits of the GABAa receptor

A 
They are ionotropic receptors (type 1) 
They have a pentameric structure consisting of the following subunits: 
· 2 x alpha 
· 2 x beta 
· 1 x gamma
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20
Q

Summarise the mechanism of action of GABAa receptors

A

GABA binding causes opening of the chloride channel leading to chloride influx
This causes hyperpolarisation of the postsynaptic neurone (inhibitory post-synaptic potential)
This causes inhibition of firing

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21
Q

What are the four main receptor proteins that make up GABAa

A

GABA receptor protein
Benzodiazepine receptor protein
Barbiturate receptor protein
Chloride channel protein

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22
Q

Describe the normal physiological action of GABA

A

GABA binds to the GABA receptor protein
GABA modulin links the GABA receptor protein and the benzodiazepine receptor protein
This results in opening of the chloride ion channel
GABA can also bind to and open the chloride channel protein directly.

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23
Q

What are the two main effects of benzodiazepines that facilitate GABA neurotransmission

A

They facilitate the GABA-mediated opening of the chloride channel
They facilitate the binding of GABA to its receptor protein (increase the affinity of GABA to the GABA binding site) – this is reciprocated

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24
Q

What are the three main effects of barbiturates that facilitate GABA neurotransmission

A

They enhance the normal physiological action of GABA
They enhance GABA binding to the GABA receptor protein (NOT reciprocated)
At higher concentrations, barbiturates can have a direct action on the chloride channel

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25
Describe the dependene of barbiturates and benzodiazepines on GABA
BDZ and Barb require GABA to some degree to function.
26
Name two drugs which act as competitive antagonists of : a) GABA b) Benzodiazepines
Competitive antagonist for GABA- Bicuculline- used mostly experimentally- competes for GABA receptor protein Competitive antagonist for Benzodiazepines -- Flumazenil- useful for reversing the toxicity of a benzodiazepine overdose
27
What type of drugs are benzodiazepines and barbiturates classed as and why
They are not agonists of GABA- but positive allosteric modulators That is they bind allosterically to the GABAa receptor and need GABA to bind also to simulate opening of the Cl- channel- they cannot do this without GABA
28
Describe the key differences in the function of benzodiazepines and barbiturates at the GABAa receptor
Different binding sites Benzodiazepines – increase the frequency of chloride channel opening Barbiturates – increase the duration of chloride channel opening Both of these mechanisms will result in greater conductance of the Cl- channel, increasing the flow of Cl- ions through the channel and thus enhancing the action of GABA.
29
What is the relative difference in selectivity between barbiturates and benzodiazepines
Barbiturates are LESS selective This may explain why barbiturates induce surgical anaesthesia and why barbiturates are less safe than benzodiazepines NOTE: barbiturates also reduce excitatory transmission (inhibit NMDA receptors) Barbiturates have other membrane effects (can open Cl- channel directly at high concs) This may also explain why Barbiturates have a low margin of safety and a narrow therapeutic window.
30
Summarise the clinical uses of benzodiazepines and barbiturates
ANAESTHETICS (BARBs ONLY : THIOPENTONE)- induction of analgesia ANTICONVULSANTS (DIAZEPAM; CLONAZEPAM; PHENOBARBITAL)- phenoarbitral is barbiturate ANTI-SPASTICS (DIAZEPAM)- act at level of spinal cord to reduce muscle tone and improve functionality ANXIOLYTICS SEDATIVES / HYPNOTICS
31
Define anxiolytic
ANXIOLYTICS: REMOVE ANXIETY WITHOUT IMPAIRING MENTAL OR PHYSICAL ACTIVITY (“MINOR TRANQUILLISERS”) No longer called minor tranquilisers as their effects aren't minor and they have no resemblance to the major tranquilisers (anti-psychotics).
32
Define sedative
SEDATIVES: REDUCE MENTAL AND PHYSICAL ACITVITY WITHOUT PRODUCING LOSS OF CONSCIOUSNESS
33
Define hypnotic
INDUCE SLEEP
34
Describe the spectrum of continuity between the anxiolytics, sedatives and hypnotics
As you increase the dose of anxiolytics you will see more sedative and hypnotic effects As you fragment the dose of hypnotics you will see more sedative and anxiolytic effects.
35
What are the ideal properties of the anxiolytics, sedatives and hypnotics
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
36
What structure is common to all barbiturates
Six-membered ring (4 carbons and 2 nitrogens) Drugs vary at R1, R2 and X
37
What is R1, R2 and X for Phenobarbitone
R1- Ethyl R2- phenyl X-OH
38
What is R1, R2 and X for Pentobarbitone
R1- Ethyl R2- 1- Methylbutyl X-OH
39
What is R1, R2 and X for Thiopentone
R1- Ethyl R2- 1-methylbutyl X- SNa
40
Describe a clinically relevant barbiturate
Amobarbital Sedative/Hypnotic used to treat severe intractable insomnia t½ 20-25h
41
Describe why barbiturates are no longer the 1st line drugs for insomnias
LOW SAFETY MARGINS  DEPRESS RESPIRATION  OVERDOSING LETHAL ALTER NATURAL SLEEP ( REM)  HANGOVERS/ IRRITABILITY ENZYME INDUCERS (effect microsomal enzymes- need to be careful of co-administration with warfarin, corticosteroids and TCAs) POTENTIATE EFFECT OF OTHER CNS DEPRESSANTS (e.g. ALCOHOL) TOLERANCE DEPENDENCE : WITHDRAWAL SYNDROME INSOMNIA ANXIETY TREMOR CONVULSIONS DEATH
42
Describe the structure of other hypnotics
OTHER HYPNOTICS CCl3CH(OH)2  CCl3CH2OH | Chloral hydrate Trichlorethanol
43
What structure is common to all benzodiazepines
They are tricyclic | Differ at R1-4
44
What are the 3 key key benzodiazepines
Diazepam Oxazepam Temazepam
45
Summarise the structure of Diazepam
R1- Cl R2- CH3 R3- H2 R4- H
46
Summarise the structure of oxazepam
R1- CL R2- H R3- OH R4- H
47
Summarise the structure of temazepam
R1-CL R2- CH3 R3- H2 R4-H
48
Summarise the general key properties of benzodiazepines
20 AVAILABLE; ALL ACT AT GABAA RECEPTORS (all have the same MoA) ALL SIMILAR POTENCIES & PROFILES PHARMACOKINETICS LARGELY DETERMINE USE
49
Describe the administration of benzodiazepines
Well absorbed per orally Peak plasma concentration after about 1 hour (slower for oxazepam) I.V. vs STATUS EPILEPTICUS- very good at reversing effects of epilepsy and seizures- want to stop this due to effects on NTs and respiration.
50
Describe the distribution of benzodiazepines
 BIND PLASMA PROTEINS STRONGLY  HIGHLY LIPID SOLUBLE  WIDE DISTN
51
Describe the metabolism of benzodiazepines
Usually extensive (liver)
52
Describe the excretion of benzodiazepines
URINE; GLUCURONIDE CONJUGATES
53
Describe the duration of action of benzodiazepines
Varies a lot This allows classification as short-acting and long-acting benzodiazepines Longer acting benzodiazepines- slower metabolism- or generation of active metabolites with benzodiazepine like activity.
54
Name the short-acting benzodiazepines
Oxazepam (8 hours) Temazepam (8 hours) Lorazepam (12 hours)
55
Name the long-acting benzodiazepines
Diazepam (32 hours) Nordiazepam (60 hours) Nitrazepam (28 hours)
56
Describe the metabolism of the short-acting benzodiazepines
Oxazepam- glucuronide Temazepam -oxazepam - glucuronide Lorazepam - glucoronide
57
Describe the metabolism of the long-acting benzodiazepines
Diazepam - temazepam - oxazepam - glucuronide Diazepam - nordiazepam - oxazepam - glucuronide chlordiazepoxide - nordiazepam - oxezapam - glucuronide Nitrazepam - glucuronide
58
Name 3 drugs that are used as anxiolytics
General rule – long-acting benzodiazepines Diazepam (Valium) Chlordiazepoxide (Librium) Nitrazepam (Mogadon)
59
What other drug can be used as an anxiolytic and under what circumstance
Hepatic impairment – this means that the benzodiazepines and metabolised more slowly – drug of choice = oxazepam
60
Name two drugs that are used as hypnotics/sedatives
General rule – short-acting benzodiazepines - don't want the patient to sleep for 24 hours Oxazepam Temazepam
61
When would you use a long-acting benzodiazepine as a hypnotic/sedative
N.B. NITRAZEPAM - DAYTIME ANXIOLYTIC EFFECT If the patient wakes up early in the morning
62
What are the advantages of benzodiazepines
WIDE MARGIN OF SAFETY OVERDOSE  PROLONGED SLEEP (ROUSABLE)- unlike barbiturates FLUMAZENIL- antidote- give IV (effects last for around 2 hours) MILD EFFECT ON REM SLEEP DO NOT INDUCE LIVER ENZYMES
63
What are the unwanted effects of benzodiazepines
SEDATION (only when used as anxiolytics), CONFUSION, AMNESIA,ATAXIA (IMPAIRED MANUAL SKILLS)- don't operate heavy machinery POTENTIATE OTHER CNS DEPRESSANTS (ALCOHOL; BARBs)- also anti-histamines TOLERANCE (LESS THAN BARBs; ‘TISSUE’ ONLY) DEPENDENCE  WITHDRAWAL SYNDROME SIMILAR TO BARBs (LESS INTENSE)  WITHDRAW SLOWLY (2 weeks -months) FREE [PLASMA]  BY e.g. ASPIRIN, HEPARIN- same binding sites on albumin
64
Compare tissue tolerance to pharmacokinetic tolerance
Tissue- pharmacodynamics- receptor densensitisation etc Pharmacokinetics- variations in metabolism, distribution, excretion Barbiturates show both types of tolerance
65
Describe how zopiclone can be used as a sedative/hypnotic
Z-drugs (make you sleep) they are cyclopyrrolones Zopiclone – this is a cyclopyrrolone and it’s short-acting (t1/2 = 5 hours) NOTE: it acts on the benzodiazepine receptor but it is not a benzodiazepine This has fewer hangover effects but dependency is still an issue - no marked effects over benzodiazepines- often used in tandem
66
Describe how antidepressants may be used as anxiolytics
SSRIs (see PT 16; Dr Croucher) LESS SEDATION & DEPENDENCE / DELAYED RESPONSE / LONG-TERM TREATMENT- generalised anxiety disorder This property of SSRIS is useful- depression and anxiety often present together- so just increase the dose of SSRI to treat both.
67
Describe some antiepileptic drugs that can be used as anxiolytics
e.g. VALPROATE, TIAGABINE | Increase GABA transmission
68
Describe how anti-psychotic drugs can be used as anxiolytics
e.g. OLANZAPINE, QUETIAPINE | But have lots of side effects
69
Describe how propranolol can be used as an anxiolytics
IMPROVES PHYSICAL SYMPTOMS TACHYCARDIA (1) TREMOR (2) Doesn't act centrally Acts on the sympathetic nervous system
70
Describe a new drug that has started to be used as an anxiolytic
Buspirone – 5HT1A agonist This has relatively few side effects and causes less sedation than benzodiazepines (less ataxia) Downside: slow onset of action (maximal anxiolytic effects are not seen for a number of days/weeks)
71
Describe how GPCRs work
GABA binds to the GABA receptor and changes its conformation so that it can bind the alpha subunit of the G protein The alpha subunit normally has GDP bound to it, when it binds to the receptor it exchanges GDP for GTP The alpha-GTP subunit is active at the target The alpha subunit breaks down GTP to GDP, which then inactivates it

Pharmacology and therapeutics (30 decks)

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