Anxiolytic, Sedative and Hypnotic Drugs Flashcards
Outline the GABA-ergic synapse neurochemistry
What does glutamate decarbxylase require to work
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
What type of molecule is GABA
AA… inhibitory NT
What tye of neurons release GABA
What is the exception
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
What receptors does GABA act on and to what effect
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)
Outline the inactivation of GABA
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)
Where are GABA-B receptors
Autoreceptors sitting on GABA presynaptic terminal, reducing GABA release and synthesis
(like a2 in the noradrenaline system)
Outline GABA metabolsim
GABA–> SUCCINIC SEMIALDEHYDE
by GABA TRANSAMINASE
SUCCINIC SEMIALDEHYDE –> SUCCINIC ACID
by SUCCINIC SEMIALDEHYDE DEHYDROGENASE (SSDH)
What is the end product of GABA metabolism and what happens to it
Succinic acid … goes back into the TCA
What is the TCA GABA shunt
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
Outline the location of enzymes involved in GABA metabolism
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
What is the consequence of imhibitors of GABA metabolism
INHIBITORS OF GABA METABOLISM
leads to a large increase in brain GABA concentration
Enhancement of GABA released from the presynaotic terminal
List two examples of GABA metabolism and the effects
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
Outline the GABA-A receptor complex
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
What happens when GABA binds to the GABA-A receptor protein
Binds to GABA receptor protein part of the complex
- 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
What does BDZ do at the GABA-A complex
Bind at the BDZ receptor protein
- 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.
- 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
What does barbiturates do at the GABA-A complex
Bind to barbiturate receptor brotein
- 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
- Enhance binding of GABA to the GABA receptor protein (but this is NOT reciprocal, so no increase in barbiturate binding following this )
- Direct action to open the chloride channel protein (at higher dosage), not the case with BDZ
How does bicuculline work
Competitve GABA receptor antagonist
How does flumazenil work
Competitive BDZ receptor antagonist (i.e. the antidote!)
T/F Barbitruates and BDZ can work without GABA
F….. they have ALLOSTERIC ACTION,
They need GABA to work
Mecahnism of action of BZs and BARBs
BZs increase FREQUENCY OF OPENINGS
BARBs increase DURATION OF OPENINGS
Ouline selectivity of BARBs and BZs
BARBs LESS SELECTIVE THAN BZs
What are the extra effects of BARBs other than GABA
Reduce EXCITATORY TRANSMISSION (some antagonistic effect of glutamate)
OTHER MEMBRANE EFFECTS (direct Cl- blocking), BDZ cannot do this
What do the extra effects of BARBs outside of GABA account for
INDUCTION OF SURGICAL ANAESTHESIA
LOW MARGIN OF SAFETY
(i.e. reducing excitatory transmission, and the cl- blocking account for this)
Clinical uses of BZs and BARBs
ANAESTHETICS (BARB only, see below)
ANTICONVULSANTS
ANTI-SPASTICS
ANXIOLYTICS
SEDATIVES / HYPNOTICS
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!
Example of anticonvulsant
DIAZEPAM; CLONAZEPAM; PHENOBARBITAL
so BDZ or BARB can be anticonvulsants!
Example of antispastic
DIAZEPAM
This has a CENTRAL action on a motor neurons coming out of the spinal cord (look at other NM blockers!)
Definition of anxiolytic drug
REMOVE ANXIETY WITHOUT IMPAIRING MENTAL OR PHYSICAL ACTIVITY (“MINOR TRANQUILLISERS”)
Define sedative drug
REDUCE MENTAL AND PHYSICAL ACITVITY WITHOUT PRODUCING LOSS OF CONSCIOUSNESS
Define hypnotic drug
INDUCE SLEEP
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
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
Structure of barbiturates
6C ring
Different side chains
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)
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
What type of tolerance occurs ith BARBs
Tissues and pharmacokinetic tolerance
Outline withdrawal symptom associated with BARBs
INSOMNIA ANXIETY TREMOR CONVULSIONS DEATH
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
Differentiate flumazenil and BDZ
Very similar structure to the BDZs but no efficacy
Effective BDZ antagonist
Where do BDZ act
Around 20 of them but all same mechanism of action
ALL ACT AT GABA-A RECEPTORS
What determines which BDZ is used
ALL SIMILAR POTENCIES & PROFILES
PHARMACOKINETICS LARGELY DETERMINE USE
Outline the administration of BDZ
WELL ABSORBED P.O.
PEAK [PLASMA] = 1hr
I.V. vs STATUS EPILEPTICUS
When might BDZ be administered IV
E.g diazepam
STATUS EPILEPTICUS
Distrubution of BDZ
BIND PLASMA PROTEINS STRONGLY
HIGHLY LIPID SOLUBLE
WIDE DISTN
Outline metabolism of BDZ
USUALLY EXTENSIVE (LIVER)
What is the excretion of BDZ
URINE; Inactive GLUCURONIDE CONJUGATES
Duration of action of BDZs
Varies greatly
Two categories of BDZ
Short acting
Long acting
SLOW METABOLISM
AND / OR
ACTIVE METABOLITES
Exampes of long acting and short acting BDZs
Long acting= diazepam (32hr)
short acting= temazepam, oxazepam (8hr)
All converted to glucuronide for excretion
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
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)
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)
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.
Advantages of BDZ
Wide margin of safety
Mild effect on REM sleep
DO NOT INDUCE LIVER ENZYMES
Why is there a wide margin of safety with BDZ
Oversose leads to ROUSABLE prolonged sleep
HAVE AN ANTIDOTE=FLUMAZENIL
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
What is the tolerance dependent on for BARB and BDZ
barb: tissue and PK
BDZ: tissue only
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)
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
Example of a non BDZ/BARB sedative/hypnotics
Mostly drugs which have other primary uses
Zopiclone
Example of other non BDZ/BARB anxiolytics
SOME ANTIDEPRESSANT DRUGS
SOME ANTIEPILEPTC DRUGS
SOME ANTIPSYCHOTIC DRUGS
PROPRANOLOL
BUSPIRONE
Duraction of zopiclone action
5hr
Where does zopiclone act
Acts at BZ receptors BUT NOT a BDZ
Class of zopiclone action
CYCLOPYRROLONE
Efficacy of zopiclone compared to BDZ
Similar
Benefit of zopiclone over BDZ
MINIMAL HANGOVER EFFECTS BUT
DEPENDENCY STILL A PROBLEM
What antidepressant drugs can be used as anxiolytics
SSRIs
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)
Example of antiepileptic drugs and why
improve
Valproate and
tiagabine (inhibits GABA reuptake… underlies anxiolytic and anticonvulsant mechanism)
Give some examples of antipsychotic drugs used as anxiolytics
OLANZAPINE, QUETIAPINE
How can propanalol help with anxiety
Physical symptoms
IMPROVES PHYSICAL SYMPTOMS
TACHYCARDIA (b1)
TREMOR (b2)
Mechanism of buspirone and advantage and disadvantage
5HT1A partial agonist
Fewer side effects (less sedation and ataxia)
Slow onset of action (days or week)
