Wk4- Sedatives (Benzos, Barbiturates) & Anaesthetics Flashcards
What is the function of the Neurotransmitter GABA?
Neurotransmitter GABA-
An inhibitory neurotransmitter which ‘rapidly inhibits central neurons through the GABA (A) Receptor’
What part of the nervous system is the Neurotransmitter GABA present in?
GABA is present in all areas of the central nervous system (mainly interneurones)
What would be the difference between a GABA Receptor:
a) Agonist
vs
b) Inverse Agonist
a) GABA Receptor Agonist= Bind & Activate the GABA Receptor so when the GABA neurotransmitter binds to its own site on the receptor, its effects are ENHANCED (reduce anxiety)
b) GABA Receptor Inverse Agonist= Binds & Activates the GABA Receptor, BUT its ‘Activation’ causes the GABA neurotransmitter to be unable to bind to its own site on the receptor. This DECREASES effects of GABA, thus increasing anxiety & seizure activity
What is the difference between the LOCATION (within nerve cells) of GABA (A) and GABA (B) Receptors?
a) GABA (A) Receptors are located Post-Synaptically
b) GABA (B) Receptors are mainly located Pre-Synaptically
What is the difference between the FUNCTION of GABA (A) and GABA (B) Receptors?
a) GABA (A) Receptors Inhibit Nerve Transmission
b) GABA (B) Receptors inhibit Neurotransmitter Release
How many sub-units are there on GABA Receptors?
GABA Receptors contain FIVE (5) Sub-Units:
2x Alpha
2x Beta
1x Gamma
What is the difference between the Neurotransmitters:
1) GABA
2) Glutamate
Neurotransmitters:
1) GABA= Inhibitory Neurotransmitter
2) Glutamate= Excitatory Neurotransmitter
The Neurotransmitters GABA & Glutamate activate receptors to affect polarisation of the cell, making the cell more/less likely to reach the threshold potential for an Action Potential
Following activation of receptors, does Glutamate make cells MORE or LESS likely to reach the threshold potential for an Action Potential?
Following activation of receptors, Glutamate make cells MORE likely to reach the threshold potential for an Action Potential. This means signal/message activity is INCREASED, thus increasing excitability and anxiety
Following activation of receptors, does GABA make cells:
a) More Positive or More Negative?
b) More Likely or Less Likely to reach the threshold potential for an Action Potential?
Following activation of receptors, GABA make cells-
a) More Negative and therefore…
b) Less Likely to reach the threshold potential for an Action Potential. This means signal/message activity is DECREASED, thus decreasing anxiety
What type of Receptor is the GABA (A) Receptor?
GABA (A) Receptor is a: Ligand-gated Ion Channel
Some drugs, like benzodiazepines, module GABA receptors to cause a ‘Conformational Change in the Receptor’. What does this mean?
Benzodiazepines cause a conformational change in the GABA receptor, meaning they change the shape of the gaba receptor site
a) Do Benzodiazepines Increase or Decrease AFFINITY of Neurotransmitter GABA binding?
b) how do they do this?
a) Benzodiazepines INCREASE the Affinity of GABA binding. This means the neurotransmitter is more likely to bind, and rates of unbinding is decreased
b) Benzodiazepines achieve this through conformational change (shape change) of the receptor
Do Benzodiazepines increase or decrease the inhibitory effects of GABA?
Benzodiazepines INCREASE the inhibitory effects of GABA
Benzodizepines potentiate the inhibitory effects of GABA. What are the 5 key effects patients experience as a result?
Benzodizepines potentiate the inhibitory effects of GABA leading to:
1- Anxiolytic effects
2- Sedative effects
3- Hypnotic effects
4- Muscle relaxant effects
5- Antiepileptic effects
Benzodiazepines are central depressants, but in contrast to other hypnotics and anxiolytics do not normally cause _____?
Benzodiazepines are central depressants but in contrast to other hypnotics and anxiolytics do not normally cause ‘fatal or severe adverse reactions’
Are benzodiazepines able to independently affect Chloride (Cl-) Conductance after binding to the allosteric modulation site?
No, when benzodiazepines bind to the allosteric modulation site, they do not affect Chloride Conductance. This means, without the neurotransmitter GABA also being bound to the receptor, benzos will not have an effect on the movement of chloride ion channel
Are barbiturates able to independently affect Chloride (Cl-) Conductance after binding to the allosteric modulation site?
Yes, when Barbiturates bind to the allosteric modulation site, they can directly affect Chloride Conductance. This means, even without the neurotransmitter GABA also being bound to the receptor, they can have an effect on the movement of chloride through the ion channel. This makes them dangerous & often fatal in overdose
Describe the step by step process of Benzodiazepines Mechanism of Action
Benzodiazepine Mechanism of Action:
1- Benzodiazepine binds to GABA(A) Receptor
2- Benzodiazepine causes a conformational (shape) change in the receptor, increasing affinity (likelihood) of GABA binding. Thus increasing how often the channel open
3- Neurotransmitter GABA binds to the GABA(A) Receptor
4- Together, the Neurotransmitter GABA & the Benzo allow the ion channel pore to open wider
5- This increases amount of chloride ions that can flow into the postsynaptic neuron
6- Chloride hyperpolarises cell & makes it more negative- this makes the cell less likely to reach threshold for an action potential
7- This inhibits its firing potential (inhibition of message firing)
8- CNS Depression & Effects of Anxiolytic, Sedation, Hypnotic, Muscle Relaxant, Antiepileptic
Where on the GABA Receptor do Benzodiazepines bind to (out of the 5 sub-units)?
Binding site of Benzodiazepines is between the alpha & gamma subunit (out of the 5 sub-units of- 2 beta, 2 alpha, 1 gamma)
Where on the GABA Receptor do Barbiturates bind to (out of the 5 sub-units)?
Binding site of Barbiturates is either on alpha or beta subunit (out of the 5 subunits- 2 beta, 2 alpha, 1 gamma)
Describe what type of drug Ketamine is? [eg. agonist/antagonist, receptor name]
Ketamine is an NMDA (Glycine) Antagonist
Ketamine is an NMDA (Glycine) Antagonist. What does this mean?
Ketamine is a NMDA (Glycine) antagonist. This means it binds to the NMDA (Glycine) receptors and BLOCKS their action. Blocking these receptors results in blocking secretion of Glutamate (an excitatory neurotransmitter)
Ketamine is a NMDA (Glycine) antagonist. This means it binds to the NMDA (Glycine) receptors and blocks their action. By doing so, it blocks the release of which neurotransmitter?
Ketamine blocks the release of the Neurotransmitter Glutamate (an excitory neurotransmitter). As a NMDA (Glycine) Agonist, Ketamine binds to the NMDA (Glycine) receptors and BLOCKS their action, thus blocking release of Glutamate
GABA Receptor Agonists (eg. Benzodiazepines) and NMDA/ Glycine Antagonists (eg. Ketamine) both depress the central nervous system & create sedation. What is the difference in their mechanism of action?
1- GABA Receptor Agonists (eg. Benzodiazepines) Binding to GABA receptors & Activating them to increase binding of neurotransmitter gaba, & thus enhance the inhibitory of GABA neurotransmitter
2- NMDA/Glycine Antagonists (eg. Ketamine) Bind to NMDA (Glycine) Receptors and Block release of Glutamate, & thus decrease the excitatory effects of Glutamate
NMDA (Glycine) Antagonists (eg. Ketamine) have been used experimentally for treatment of what?
NMDA (Glycine) Antagonists (eg. Ketamine) have been used experimentally for treatment of Brain damage secondary to strokes & head injuries, as well as for epilepsy
Why are NMDA (Glycine) Antagonists (eg. Ketamine) problematic?
Because they have a tendancy to cause hallucinations and other disturbances
What are the 3 main components of the ‘Anaesthetic State’
Anaesthetic State-
1- Analgesia
2- Loss of Consciousness
3- Muscle Relaxation
Anesthesia generally consists of 3 main phases. What are they?
Anesthesia 3 main phases:
1- Induction
2- Maintenance
3- Recovery
Prolonged induction of anaesthesia can produce a period of ___ before anaesthesia
Prolonged induction of anaesthesia can produce a period of EXCITEMENT before anaesthesia
What usually happens to a patients breathing in the period following the Induction of General Anaesthesia (the 1st Phase)?
Following induction (of General Anaesthesia), a period of apnea follows, and is succeeded by slow & shallow breathing
What is the Mechanism of Action of most General Anaesthetics?
[Hint- what is their effect on different neurotransmitters?]
The Mechanism of Action of most General Anaesthetics is to:
1- Enhance the activity of the inhibitory neurotransmitter GABA
2- Inhibit the activity of the excitatory neurotransmitter GLUTAMATE
What are 3 secondary effects of the Muscle Relaxation that intravenous anaesthetic agents can produce?
Effects of General Anaesthetic-
1. Muscle Relaxation causing:
1a- Respiratory Depression
1b- Laryngeal Reflex
1c- Cardiovascular Depression
What are the pros & cons of Thiopentone (a General Anaesthetic)?
Thiopentone (a General Anaesthetic)-
Pros= Rapid Onset
Cons= Slow recovery, & can cause Laryngospasm
What are the pros & cons of Propofol (a General Anaesthetic)?
Propofol (a General Anaesthetic)-
Pros= Fast onset, & Fast recovery
Cons= High rates of Hypotension, & Injection pain
What are the pros & cons of Midazolam (when used as a General Anaesthetic)?
Midazolam (a General Anaesthetic)-
Pros= Amnesic effects
Cons= Least effective general anaesthetic
What are 4 examples of inhaled anaesthetic agents?
Inhaled Anaesthetic Agents-
1- Methoxyflurane
2- Nitrous Oxide
3- Halothane
4- Xenon (Nitrogen Narcosis)
The ‘Anaesthetic Potency’ of Inhaled Anaesthetics is directly correlated with what?
The ‘Anaesthetic Potency’ of Inhaled Anaesthetics is directly correlated with LIPID SOLUBILITY, rather than chemical structure
“The Mechanism of action of Inhaled Anaesthetics is unknown, but is thought to be largely to do with interaction with ____”
Mechanism of action is unknown but is thought to be largely to do with interaction with ligand-gated open channels (eg. GABA receptors)
What is the ‘Minimum Alveolar Concentration’ in relation to Inhaled Anaesthetics?
Minimum Alveolar Concentration=
This MAC is a measure of the alveolar concentration that prevents movement in response to a skin incision in 50% of patients. It is a measure of potency and is inversely related
What are the risks associated with Nitrous Oxide (an Inhaled Anaesthetic)?
Risks of Nitrous Oxide:
1- Suppression of bone marrow
What are the risks associated with Halothane (an Inhaled Anaesthetic)?
Risks of Halothane:
1- Dysrhythmias
2- Liver Damage
What are the risks associated with Isoflurane (an Inhaled Anaesthetic)?
Risks of Isoflurane:
1- Irritation of respiratory tract
2- Myocardial ischaemia
What are the risks associated with Methoxyflurane (an Inhaled Anaesthetic)?
Risks of Methoxyflurane:
1- Nephrotoxicity (secondary to inorganic fluoride being released after metabolism)
What causes Nephrotoxicity in inhaled anaesthetics like Methoxyflurane?
Nephrotoxicity from Methoxyflurance occurs secondary to inorganic fluoride being released after metabolism
