Anxiolytics and hypnotics Flashcards
What do these drugs target to give them their anxiolytic and hypnotic properties
They enhance GABA transmission.
What are the two main classes of GABA receptor and where are they found
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)
Which other drug classes can have anxiolytic and sedative effects
Anti-depressants
Anti-psychotics
Anti-convulsants
What type of amino acid is GABA
Neutral
Why is GABA called GABA
Gamma amino butyric acid
This is because the amino group is on the gamma carbon of GABA
Describe the distribution of GABA neurones
Cerebral cortex Cerebellum Hippocampus Corpus striatum Hypothalamus Dorsal horn of spinal cord Relatively little in the PN
Describe the morphology of GABA neurones
They are generally short inhibitory interneurons
They inhibit the activity of localised regions (e.g they may inhibits hyperexcitabilty of the hippocampus)
Where can you find longer GABA tracts
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
Summarise the functions of GABA neurones in terms of CNS activity
Emotional control
Motor control
Extrapyramidal activity
Endocrine function
Describe the synthesis of GABA in the pre-synaptic terminal of a GABAergic neurone
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.
Describe the release of GABA into the synapse
AP arrives- Ca2+ mediated exocytosis of vesicles containing GABA
- 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
Describe the reuptake of GABA from the synaptic cleft
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.
Describe the metabolism of GABA after re-uptake into the synaptic cell or glial cell
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
What does GABA reuptake depend on
Sodium dependent
Energy dependent
Describe the GABA shunt
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
Where are the enzymes involved in GABA synthesis and metabolism located
GAD- cytosol
GABA-T and SSDH- mitochondrial membrane
What is a consequence of inhibiting the enzymes of GABA metabolism
An increase in the amount of GABA available in the brain.
Name two drugs that interfere with GABA metabolism and can be used as anti-covalents
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
Describe the different subunits of the GABAa receptor
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
Summarise the mechanism of action of GABAa receptors
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
What are the four main receptor proteins that make up GABAa
GABA receptor protein
Benzodiazepine receptor protein
Barbiturate receptor protein
Chloride channel protein
Describe the normal physiological action of GABA
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.
What are the two main effects of benzodiazepines that facilitate GABA neurotransmission
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
What are the three main effects of barbiturates that facilitate GABA neurotransmission
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
Describe the dependene of barbiturates and benzodiazepines on GABA
BDZ and Barb require GABA to some degree to function.
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
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
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.
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.
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
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).
Define sedative
SEDATIVES: REDUCE MENTAL AND PHYSICAL ACITVITY WITHOUT PRODUCING LOSS OF CONSCIOUSNESS
Define hypnotic
INDUCE SLEEP
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.
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
What structure is common to all barbiturates
Six-membered ring (4 carbons and 2 nitrogens)
Drugs vary at R1, R2 and X
What is R1, R2 and X for Phenobarbitone
R1- Ethyl
R2- phenyl
X-OH
What is R1, R2 and X for Pentobarbitone
R1- Ethyl
R2- 1- Methylbutyl
X-OH
What is R1, R2 and X for Thiopentone
R1- Ethyl
R2- 1-methylbutyl
X- SNa
Describe a clinically relevant barbiturate
Amobarbital
Sedative/Hypnotic used to treat severe intractable insomnia
t½ 20-25h
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
Describe the structure of other hypnotics
OTHER HYPNOTICS CCl3CH(OH)2 CCl3CH2OH
Chloral hydrate Trichlorethanol
What structure is common to all benzodiazepines
They are tricyclic
Differ at R1-4
What are the 3 key key benzodiazepines
Diazepam
Oxazepam
Temazepam
Summarise the structure of Diazepam
R1- Cl
R2- CH3
R3- H2
R4- H
Summarise the structure of oxazepam
R1- CL
R2- H
R3- OH
R4- H
Summarise the structure of temazepam
R1-CL
R2- CH3
R3- H2
R4-H
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
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.
Describe the distribution of benzodiazepines
BIND PLASMA PROTEINS STRONGLY HIGHLY LIPID SOLUBLE WIDE DISTN
Describe the metabolism of benzodiazepines
Usually extensive (liver)
Describe the excretion of benzodiazepines
URINE; GLUCURONIDE CONJUGATES
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.
Name the short-acting benzodiazepines
Oxazepam (8 hours)
Temazepam (8 hours)
Lorazepam (12 hours)
Name the long-acting benzodiazepines
Diazepam (32 hours)
Nordiazepam (60 hours)
Nitrazepam (28 hours)
Describe the metabolism of the short-acting benzodiazepines
Oxazepam- glucuronide
Temazepam -oxazepam - glucuronide
Lorazepam - glucoronide
Describe the metabolism of the long-acting benzodiazepines
Diazepam - temazepam - oxazepam - glucuronide
Diazepam - nordiazepam - oxazepam - glucuronide
chlordiazepoxide - nordiazepam - oxezapam - glucuronide
Nitrazepam - glucuronide
Name 3 drugs that are used as anxiolytics
General rule – long-acting benzodiazepines
Diazepam (Valium)
Chlordiazepoxide (Librium)
Nitrazepam (Mogadon)
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
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
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
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
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
Compare tissue tolerance to pharmacokinetic tolerance
Tissue- pharmacodynamics- receptor densensitisation etc
Pharmacokinetics- variations in metabolism, distribution, excretion
Barbiturates show both types of tolerance
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
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.
Describe some antiepileptic drugs that can be used as anxiolytics
e.g. VALPROATE, TIAGABINE
Increase GABA transmission
Describe how anti-psychotic drugs can be used as anxiolytics
e.g. OLANZAPINE, QUETIAPINE
But have lots of side effects
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
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)
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
