Anxiolytics, Sedatives and Hypnotics (04.02.2020) Flashcards
How is GABA synthesised?
- from glutamate (which is the most dominant excitatory NT)
- GAD turns glutamate to GABA
- GABA stored in vesicles
- released after stimulus
- acts on GABAR
- uptake by presynaptic cell or glial cell.
GABA-T
GABA transaminase
breaks GABA down into SSA
GABA neurones
- generally short axon interneurones
- localised short axon interneurones
- there are some longer tracts (e.g. descending nigro-striatal pathway is a GABAergic tract that regulates the substance nigra activation, but this is different from the dopaminergic nigrostriatal pathway)
GABA neurones
- generally short axon interneurones
- inhibitory neurones
- localised short axon interneurones
- there are some longer tracts (e.g. descending nigro-striatal pathway is a GABAergic tract that regulates the substance nigra activation, but this is different from the dopaminergic nigrostriatal pathway)
SSA
SUCCINIC SEMIALDEHYDE
SSDH
SUCCINIC SEMIALDEHYDE DEHYDROGENASE
SSA -> Succinic acid (goes back into the TCA cycle in the neurone)
What is the GABA shunt?
- GABA broken down by TCA cycle goes back into the TCA cycle.
- GABA is formed in vivo by a metabolic pathway referred to as the GABA shunt
- The GABA shunt is a closed-loop process with the dual purpose of producing and conserving the supply of GABA.
Which enzymes in the metabolism of GABA are mitochondrial and which ones are cytoplasmic?
GABA-T and SSDH are mitochondrial
GAD is cytoplasmic
What is special about GABA neurones?
GAD can be used for mapping GABA neurones in the brain.
??? is this true?
INHIBITORS OF GABA METABOLISM
large increase in brain GABA
examples:
- sodium valproate (epilim)
- vigabatrin (sabres)
Sodium Valporate - MoA
- multiple actions
- Inhibits GABA transaminase → ↑ GABA → decreased neuronal excitability
- Inactivates Na+ channels
Vigabatrin - MoA
- inhibits the breakdown of GABA (irreversible inhibition of GABA-T)
- increases the amount of GABA in the brain.
Which proteins make up the GABA receptor?
- GABA R protein
- BDZ R Protein
- Barbituate R protein
- chloride channel protein
- GABA modulin
Benzodiazepines MoA
- binds o BDZ R protein
- enhances the normal action of GABA on chloride channel protein
- in the presence of BDZ there is an increased affinity for GABA
- in the presence of GABA there is increased BDZ protein (reciprocation)
Barbituates MoA
- increase affinity for GABA
- no reciprocation, no change ind Barb binding
- at higher concentrations you can get a direct opening of chloride channel opeming
- this last one does not happen with BDZs
Bicuculline
- competes with GABA for binding site
Flumazenil
- competes with Benzodiazepines for binding site.
- useful for BDZ overdose due to competition for binding site.
BZs and Barbs
- they are not agnosists, they have no effects on the GABA R alone
- allosteric (different site)
- bind by enhancing the effect of GABA
- PAMs (positive allosteric modulators)
PAMs
positive allosteric modulatos
-> enhance the effects of GABA (not agnosts, they bind to a different site)
MoA differences in Benzos and BDZs
- BZs -> increased FREQUENCY OF OPENINGS
- BARBs increased DURATION OF OPENINGS
Selectivity of Barbs and Benzos
- BARBs LESS SELECTIVE THAN BZs
- > decreased EXCITATORY TRANSMISSION
- > OTHER MEMBRANE EFFECTS
- MAY EXPLAIN
- INDUCTION OF SURGICAL ANAESTHESIA (barbs do this and notbenzos?)
- low margin of safety
Clinical uses
- ANAESTHETICS (BARBs ONLY : THIOPENTONE)
- ANTICONVULSANTS (DIAZEPAM; CLONAZEPAM; PHENOBARBITAL)
- ANTI-SPASTICS (DIAZEPAM)
- ANXIOLYTICS
- SEDATIVES / HYPNOTICS
Anxiolytics definition
REMOVE ANXIETY WITHOUT IMPAIRING MENTAL OR PHYSICAL ACTIVITY (“MINOR TRANQUILLISERS”)
Definition of sedatives
REDUCE MENTAL AND PHYSICAL ACITVITY WITHOUT PRODUCING LOSS OF CONSCIOUSNESS
Definition of hypnolytics
INDUCE SLEEP
What should these drugs ideally do?
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’ (drowsy, irritable effect the following day)
vi) NOT PRODUCE DEPENDENCE
Barbituates - unwanted effects
- not drugs of first choice
- low safe margins (depress respiration; overdose can be lethal)
- alter natural sleep, decrease REM, -> hangovers and irritability
- Enzyme inducers (influence other drugs - be careful with co-admin)
- POTENTIATE EFFECT OF OTHER CNS DEPRESSANTS (e.g. ALCOHOL)
- Tolerance
- DEPENDENCE : WITHDRAWAL SYNDROME (insomnia, anxiety, tremor, convulsions, death)
Enzyme inducers
- An enzyme inducer is a type of drug that increases the metabolic activity of an enzyme either by binding to the enzyme and activating it, or by increasing the expression of the gene coding for the enzyme.
- It is the opposite of an enzyme repressor.
Clinical use of Barbs
- sedative / hypnotic (amobarbital, severe intractable insomnia t1/2= 20-25 h)
- anaesthetics (thiopentone)
- anxiolytics
- anticonvulsants
Benzodiazepines
- 20 available
- All act on GABAA R
- All have similar potencies and profiles
- Pharmacokinetics largely determine use
- Duration of action varies greatly (there are short and long acting)
Benzos structur
- 3 ring structure (diazepine and benzene ring together)
- flumenazil has a similar structure but with a chain that makes it an antagonist.
Administration of Benzos
- WELL ABSORBED orally
- PEAK [PLASMA] is around 1h
- I.V. vs STATUS EPILEPTICUS
Distribution of Benzos
- BIND PLASMA PROTEINS STRONGLY
- HIGHLY LIPID SOLUBLE -> Wide distribution
Key long acting Benzo?
Diazepam
What are some shrt acting Benzos?
- oxazepam
- temazepam
Which drugs are used as anxiolytics?
- long acting benzos
- diazepam (valium)
- chlordiazepoxide (librium)
- nitrazepam
- n.b. oxazepam given if there is any hepatic impairment (metabolism is not that good, acts longer)
Which drugs are used as sedatives/hypnotics?
- short acting benzodiazepines
- temazepam
- oxazepam
- nitrazepam - daytime anxiolytic effects (t1/2 is 28h)
What are the advantages of Benzos?
- wide margin of safety
- overdose -> prolonged sleep (rousable)
- flumazenil can revers
- mild effect on REM sleep
- not enzyme inducers:
DO NOT INDUCE LIVER ENZYME
Unwanted effects of benzodiazepines
- SEDATION, CONFUSION, AMNESIA,ATAXIA (IMPAIRED MANUAL SKILLS) -> not good for people that work manually or handle machinery
- POTENTIATE OTHER CNS DEPRESSANTS (ALCOHOL; BARBs)
- TOLERANCE (LESS THAN BARBs; ‘TISSUE’ ONLY)
- DEPENDENCE: Withdrawl syndrome SIMILAR TO BARBs (LESS INTENSE) -> take off the drug gradually -> WITHDRAW SLOWLY
- FREE [PLASMA], increased by e.g. Aspirin, Heparin
ZOPICLONE
- SHORT ACTING (t½ around 5h)
- ACTS AT BZ RECEPTORS (CYCLOPYRROLONE)
- SIMILAR EFFICACY TO BZs
- MINIMAL HANGOVER EFFECTS BUT DEPENDENCY STILL A PROBLEM
Z-drugs
= a group of nonbenzodiazepine drugs with effects similar to benzodiazepines.
- useful as hypnotics (used for sleeping problems)
- e.g. zopiclonead
- hope was a reduction in dependancy however patients do become dependant
- there are not that many
Name different sedatives / hypnotics
- tamazepam (short acting benzo)
- oxazepam (short acting benzo)
- zopiclone (and other z-drugs)
- am-barbital (barb)
Name different anxiolytics
- Diazepam (valium)
- Chlordiazepoxide (Librium)
- Nitrazepam (daytime anxiolytic effect)
- n.b. Oxazepaam in people with impaired liver function
- some antidepressant drugs e.g. SSRIs
- some anti-epileptic drugs e.g. valproate, tiagabine
- some anti-psychotic drugs (e.g. olanzapine, quetiapine)
- propanolol (improved physical symptoms including tachycardia (b2) and tremor (b2))
- Buspirone (5HT1A agonist, few SE and
SBA 1:
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
C
SBA 2: Which of the following drugs is commonly used in the treatment of insomnia?
A: Thiopental B: Phenytoin C: Baclofen D: Sodium valproate E: Temazepam
E
SSRIs as anxiolytics
- less sedation and dependance
- delayed response (this is the downside)
- long term treatment
- co-treatment of depression and anxiety??? find out.
What are the key differences between benzodiazepines and barbiturates?
- Barbituates increase the duration of Cl- channel opening, benzos increase the frequency
- Benzodiazepines have an antidote (flumenazil)
- barbituates are less selective, have a lower margin of safety
- benzodiazepines have a wider range of safety
Structure of barbituates
1 ring with functional groups
Administration of benzodiazepines
- WELL ABSORBED P.O.
- PEAK [PLASMA] around 1h
- I.V. vs STATUS EPILEPTICUS
Distribution of benzodiazepines
BIND PLASMA PROTEINS STRONGLY
HIGHLY LIPID SOLUBLE -> wide distribution
Metabolism and excretion of benzodiazepines
- METABOLISM: usually extensive (liver)
- EXCRETION: urine; glucuronide conjugates.
How do long acting benzos work?
- slow metabolism and/or active metabolites
Busipirone
- 5HT1A AGONIST
- FEWER SIDE-EFFECTS (< SEDATION)
- SLOW ONSET OF ACTION (DAYS / WEEKS)
=> used as an anxiolytic
MoA:
Propranolol
=> can be used as an anxiolytic
IMPROVES PHYSICAL SYMPTOMS
TACHYCARDIA (b1)
TREMOR (b2)
Thiopentone
- barbiturate
- used as an anaesthetic
Which drug class can also be used as anaesthetics?
Barbs only (e.g. thiopentone)
What are aspects of the withdrawal syndrome seen in withdrawn of barbs?
Insomnia Anxiety Tremor Convulsions Death
What are bentos eventually metabolised to?
Glucuronide
