sedatives and anxiolytics Flashcards
1
Q
What is a neurotransmitter?
A
A chemical substance released at the end of a nerve fibre by the arrival of a nerve impulse to another nerve fibre, muscle fibre or some other structure
2
Q
What is an excitatory neurotransmitter?
A
Increases the probability that the target cell will fire an action potential
3
Q
Give an example of an excitatory neurotransmitter:
A
Glutamate
4
Q
What is an inhibitory neurotransmitter?
A
Decreases the probability that the target cell will fire and action potential
5
Q
Give two examples of inhibitory neurotransmitters:
A
GABA (fast, found in virtually every part of the brain = short interneurones e.g. pain modulation)
Glycine (the inhibitory transmitter in the spinal cord)
6
Q
Anxiety is a disorder of the…
A
CNS
Too few GABA = Anxiety
7
Q
What was GABA first discovered as?
A
A product of microbial and plant metabolism
8
Q
Which drug enhances the effects of GABA?
A
Valium
9
Q
What causes epilepsy?
A
When GABA is lacking in certain parts of the brain
10
Q
Where are there long GABAergic tracts to?
A
Cerebellum
Striatium
11
Q
Which enzyme produces GABA?
A
Glutamic Acid Decarboxylase (GAD) -> found primarily in CNS
Co-enzyme = Vitamin B6
12
Q
Which reaction produces GABA?
A
Glutamate -> GABA + CO2
13
Q
How many isoforms of Glutamic Acid Decarboxylase are found in the brain?
A
Two
(GAD1 & GAD2 -> evolved separately but do same job!)
14
Q
What is a glial cell?
A
A helper axillary cell = mop up and release neurotransmitter
15
Q
What breaks GABA down?
A
GABA-Transaminase (GABA-T)
Co-factor = Vitamin B6= located in the mitochondria
16
Q
What does GABA-T break GABA down into?
A
L-glutamate
17
Q
Which drug is the most potent inhibitor of GABA-T?
A
Gabaculine (used more in lab than clinically)
18
Q
What happens inside the cell after Gabaculine is given?
A
- Lots of GABA in cleft
- Eventually it stops vesicles containing GABA (relies on action of GAD to package produce GABA from glutamate and package into vesicle) = action potential = no release of GABA = no inhibition = Anxiety
19
Q
Which cells express GABA receptors?
A
- Most neurones in the CNS
- Glial cells (astrocytes) = ANS neurones
20
Q
When GABA binds what happens to the neurone?
A
Shift in membrane permeability to Chloride ions
postsynaptic inhibition = hyperpolarisation
presynaptic inhibition = depolarisation
21
Q
How many types of GABA receptor are there?
What are they called?
A
Two
GABA-A & GABA-B
22
Q
What type of receptor is GABA-A?
A
Ligand-gated ion (chloride) channel
23
Q
What type of receptor is GABA-B?
A
GPCR
24
Q
Which drug does GABA enhance the binding of?
A
Benzodiazepine
25
Why does GABA enhance binding of benzodiazepine?
GABA-A and Benzodiazepine (BDZ) receptor make up 2 separate parts of the same complex
26
Which is the most prevalent GABA receptor?
GABA-A
27
How many subunits does the GABA-A receptor have?
5 (pentameric)
N.b. subunit composition varies between brain regions and neuronal subpopulations (how we get sensitivity to specific regions)
28
Between which two subunits on the GABA-A receptor do benzodiazepines bind?
Alpha & Gamma
29
Which subunit of the GABA-A receptor binds GABA?
Alpha
30
Whats the birds eye view subunit arrangement for the GABA-A receptor?
31
What are the two types of allosteric modulators that act on GABA-A receptors?
Channel blockers (picrotoxin)
Channel modifiers (ethanol, volatile anaesthetics & neurosteroids)
32
What is the most common arrangement of subunits in GABA-A receptors?
1 X Alpha
2 X Beta
2 X Gamma
33
What are the different effects of benzodiazepine on GABA-A receptors with different subunits?
No effect = Alpha 4 & 6
Sedation and Amnesia = Alpha 1
Anxiolytic = Alpha 2 &3
For sensitivity to benzodiazepine = Gamma 2
34
Where are GABA-A receptors found?
Postsynaptic membrane
35
Where are GABA-B receptors found?
Presynaptic terminals
(many sites in brain & periphery)
36
When GABA binds to GABA-B receptors what happens?
- inhibition of voltage sensitive Ca channels
- inhibition of transmitter release
37
What type of receptor is the Glycine receptor?
Ligand gated Cl channel
38
What is the role of Glycine in interneurones?
High in ventral horn
Low in ventral root fibres= associated with inhibitory interneurones
N.B. inhibitory effect of glycine is restricted to spinal cord, lower brain stem and retina
39
What is the role of Glycine in the CNS?
inhibitory hyperpolarisation
N.B. inhibitory effect of glycine is restricted to spinal cord, lower brain stem and retina
40
What type of neurotransmitter is Glycine?
Inhibitory
41
Name 3 amino acids that activate the glycine receptor:
Glycine
Beta alanine
Taurine
42
Name two competitive agonists of the Glycine receptor:
Strychnine (high affinity)
Caffiene= block the receptor
43
Which receptors mediate the excitatory responses facilitated by Glycine?
NMDA receptors
44
What effects do glycine/NMDA receptor antagonists have?
Anxiolytic
45
What 4 features characterise anxiety disorders?
- Excessive rumination
- Worrying
- Apprehension
- Fear
46
Which four aspects of experiences does "anxiety" cover?
- mental apprehension
- physical tension
- physical symptoms
- dissociative anxiety
47
What are the (5) somatic and autonomic clinical manifestations of anxiety?
- Restlessness and agitation
- Tachycardia
- Increased sweating
- Weeping
- GI disorders
48
Which three disorders can anxiety disorder be divided into?
- Generalised anxiety disorder
- Phobic disorder
- Panic disorder(characterised by own symptoms and have own treatment)
49
What are the 6 clinically recognised anxiety disorders?
1. **_generalised anxiety disorder_** = ongoing anxiety lacking any clear reason or focus
2. **_social anxiety disorder_** = fear of being with/interacting with other people
3. **_Panic disorder_** = sudden attacks of overwhelming fear
4. **_Phobias_** = song fears of specific objects/ situations
5. **_Post traumatic stress disorder_** = anxiety triggered by recall of past stressful experiences
6. **_Obsessive compulsive disorder_** = compulsive ritualistic behaviour driven by irrational anxiety
50
Which types of drugs are used to treat anxiety disorders?
Anxiolytics -\> anxiety
Sedatives -\> sedation (calming effect)
Hypnotics -\> insomnia (induce sleep)
51
How does dose effect anti-anxiety drugs?
Effect can be dose dependent
= same drug can be classified as anxiolytic/sedative/hypnotic at different dose
52
Too much anti-anxiety drugs =
seizures/ anxiety
53
What are the two possible mechanisms for anxiety?
1. over activation of brain neurotransmission and neuronal firing (too much excitation e.g. excess glutamate & calcium)
2. under-inhibition of brain neurotransmission and neuronal firing (insufficient inhibition e.g. insufficient GABA, GABA-A receptor function or enhancement of GABA)
54
How do many sedative/tranquillising drugs work?
Enhance the effects of GABA:
* increased GABA = blocks repute & increased GABA release
* increased GABA signalling = Benzodiazepine agonist (partial/total) or blocking benzodiazepine inverse agonists
55
Name 4 groups of anxiolytic drugs:
* Phenobarbitone :
* Barbiturate
* Benzodiazepines
* Older Tricyclic antidepressants (TCAs)
* imipramine
* doxepin
* amitryptiline
* trazodone
* Monoamine Oxidase inhibitors (MAOIs)
* phenezine
* tranylcypromine
* Selective serotonin reuptake inhibitors (SSRIs)
* sertraline
* fluoxetine
* citalopram
* paroxetine
56
Which receptor do barbiturates bind to?
Beta subunit of GABA-A
(ligand gated Cl channel) = increased duration of Cl channel opening
57
What are the 4 actions of barbiturates?
- potentiate GABA (increased duration of Cl opening)
- block AMPA receptor (glutamate receptor subtype)
- inhibit Ca dependent release of neurotramsmitters
- Binds entire superfamily of ligand gated ion channels
58
What are the 2 side effects of Barbiturates?
Sedation and hypnotic (too much inhibition)
Risk of abuse and addiction is high (rarely used anymore)
59
When are Barbiturates used clinically?
Short-term treatment of severe insomnia
(when benzodiazepines or non-benzodiazepines have failed)
60
What are the 5 clinical uses of benzodiazepines?
- anti anxiety
- sedative
- hypnotic
- anticonvulsant
- muscle relaxant
61
What are the 6 side effects of benzodiazepines?
- Drowsiness
- Confusion
- Amnesia
- Impaired motor co-ordination
- Lack of depth perception
- Reduced REM (rapid eye movement) sleep
62
In which two treatments are benzodiazepines often used?
As a premedication for medical or dental procedures
63
What are the three different categories of benzodiazepines?
Short-acting
Intermediate-acting
Long-acting
64
Which two categories of benzodiazepines are preferred for insomnia?
Short & intermediate-acting
65
Which category of benzodiazepines is preferred for anxiety?
Long-acting
66
What happens following longer term use of benzodiazepines?
Tolerance, dependence & withdrawal
Psychological & physical effects
67
Which receptor interactions with benzodiazepines may contribute to their addictive properties?
inhibits NMDA & nACh receptors
68
Overall which is less toxic... barbiturates or benzodiazepines?
Benzodiazepines
BUT... combination with other CNS depressants (alcohol & opiates) = increased toxicity and potential of fatal overdose
69
Why do we rarely use the older tricyclic antidepressants (TCAs)?
Severe side effects
70
Name 4 different older tricyclic antidepressants (TCAs):
- imipramine
- doxepin
- amitryptiline
- trazodone
71
Name 2 different Monoamine oxidase inhibitors (MAOs):
- phenelzine
- tranylcpromine
very effective for anxiety but lots of drug dangers so rarely prescribed
72
What is the main problem with selective serotonin reuptake inhibitors (SSRIs)?
Early in treatment they can produce anxiety due to negative feedback through serotonergic auto receptors
(reduced by combined with a low dose of benzodiazepine)
73
Name a 5HT-1A receptor partial agonist used as an anxiolytic drug:
Buspirone
74
What are the 4 side effects for Buspirone?
Nausea
Dizziness
Headache
Restlessness
(less than benzodiazepines)
75
What are the 3 key let downs for Buspirone?
* Takes days/weeks to develop action
* Ineffective against panic attacks
* Prolonged use = adaptive changes/ desensitisation
76
What are the 3 key benefits of Buspirone?
* No reports of tolerance and physical dependence
* Less sedation
* Less motor incoordination
77
Name two hypnotics used to treat insomnia:
* Zopiclone (non BDZ hypnotic)
* Zolpidem (non BDZ hypnotic imidazopyridine)
78
Name three antihistamines used for sedation:
Chloral hydrate
Diphenhydramine (nytol)
Promethazine
n.b. Drowsiness = side effect due to H1 antagonism in CNS
79
What are the 2 benefits of antihistamines over other sedatives?
Fewer side effects
Safer
80
Name a beta adrenoreceptor antagonist used to remove the peripheral symptoms of anxiety:
Propanalol
81
Why are anxiolytics often used in general dental practice?
As a premedication
82
What are the 6 indications of using anxiolytics in general dental practice?
If individual is:
* fearful
* anxious
* longer appointments
* especially invasive procedures
* pronounced gag reflex
* may help achieve profound local anaesthesia
83
What are the 5 contraindications of using anxiolytics in general dental practice?
* pregnancy
* elderly
* medically unstable (angina/diabetes)
* medically complex (sever systemic disease)
* patients already presenting adverse reactions to medications
84
Which anxiolytics are often used in general dental practice?
Chloral hydrate (now replaced with Midazolam)
Barbituates = phentobarbital
Benzodiazepines = Diazepam (valium), Lorazepam (ativan) & Triazolam
Antihistamine H1 - hydroxyzine (vistoril)
Serotonin 5-HT-1A partial antagonists = Buspirone
85
What is the mechanism of action for Benzodiazepines?
Increase the PROBABILITY of channel opening
86
What is the mechanism of action for phenobarbitone (barbiturates)?
Low conc = PROLONG channel opening High conc = open channel in absence of GABA
