General anaesthetics Flashcards
What does NO do in terms of pain?
Reduced RESPONSE to pain
What does ether do in terms of pain?
Reduced RESPONSE to pain
Loss of consciousness
What does Chloroform do in terms of pain?
Reduced RESPONSE to pain
Loss of consciousness
What is the structure of ether and chloroform?
Volatile liquids that turn to gas at room temperature
How are general anaesthetics described?
Into 2 categories - by the route of administration
1) Chemical
2) Physical
What are chemical general anaesthetics?
Examples?
1) Inhalational
- NO
2) Intraveous
- Steroids
- Barbiturates
- Halogenated hydrocarbons
What are the physical general anaesthetics?
- Low-pressure
- Hypothermia
What do general anaesthetics do/not do?
- Reduces the RESPONSIVENESS to pain
- NOT the FEELING of pain
How do we know that anaesthetics don’t work by working on a specific receptor?
- The structure of general anaesthetics is VERY DIVERSE
- If work on a specific receptor - normally have a CONSERVED structure
How easily do general anaesthetics enter into membranes?
Why?
Easily
They are very lipophilic
What is the potency of general anaesthetics depends upon?
Closely related to the oil:gas partition coefficient (how easily they enter into the lipids)
What is MAC?
Minimum alveolar concentration
The amount of the drug needed to achieve a state of anaesthesia in 50% of proteins
Which anaesthetics have the highest potency?
Anaesthetics with the highest lipid solubility
How does temperature impact on anaesthesia?
Decrease temperature –> anaesthetic effect
What is the lipid theory of anesthetic action?
‘Molecules exert their action in the nervous system by entering into the plasma membrane
What are the 2 ideas of the ‘lipid theory’?
1) Membrane expansion
2) Increase in lipid fluidity
What is the ‘membrane expansion’ component of the lipid theory?
Lipids enter into the membrane
Causing:
- Fat molecules in the membrane to be pushed apart
- Altering the property of the neurons
- Altering neuronal excitability –> entering the state of anaesthesia
What is the ‘increase in lipid fluidity’ component of the lipid theory?
Lipids enter into the membrane
Causing:
- Lipids to become more ‘floppy’
- Activity of the proteins within the lipids are impacted
- Effect neuronal excitability –> entering the state of anaesthesia
What are the 3 arguments for the ‘lipid theory’?
- Obey the Meyer-Overton rule
- Obey the pressure effect
- Support drug diversity
What is the Meyer-Overton rule?
Correlation between the oil:gas coefficient and the potency of the drug as a general anaesthetic
What is the pressure effect on general anaesthetics?
- Reducing the atmospheric pressure INCREASES the potency of general anaesthetics
- As reduce pressure - support a more fluid membrane
How does the lipid theory support drug diversity?
- All general anaesthetics have a diverse structure
- Therefore the only thing that would affect how well they work would be how well they enter the lipid membrane
What are the 4 arguments against the the ‘lipid theory’?
1) Temperature effect
2) Binding sites
3) Loss of activity with homologous series of lipophilic compounds
4) Some drugs increase GABAa receptor affinity for agonists
Why does the temperature effect oppose the lipid theory?
- When the temperature decrease - membranes become LESS fluid
- But decrease temperature –> has anaesthetic effect
- Counteracts the effect that general anaesthetics work by increasing membrane fluidity
How do ‘binding sites’ counteract the ‘lipid theory’?
- Can see SATURATION of effect when drugs are administered
- Saturation is a classic indication of a drug that is working on a RECEPTOR, where there is a limited amount
What did the oppositions of the ‘lipid theory’ give rise to?
Describe this theory
The ‘protein theory’ of general anaesthetics
There is a RECEPTOR that the drugs must bind to to exert their action
Which receptors do some anaesthetics bind to?
What do they do here?
GABAa receptors
They alter the function of the GABAa receptors
Why is the lipid solubility of the drug so important?
The amino acids present that the general anaesthetics interact with are part of the channel within the transmembrane domain - buried deep within the plasma membrane
Where do gaseous anaesthetics tend to bind?
At the INTERFACE between 2 subunits of the GABAa receptor
Where do intravenous anaesthetics tend to bind?
Bind just the beta subunit
As well as GABAa receptors, where else can general anaesthetics bind?
- Low concentrations can activate the TwoPoreDomain K channels
- NDMA glutamate receptors
What are the TwoPoreDomain K channels involved in?
What happens when these channels are activated by GAs?
Maintaining the resting, hyper polarised state of the neurons
When activated - hyper polarise the channels –> less likely to fire action potentials
What blocks NDMA glutamate receptors?
NO and Ketamine
What blocks NDMA glutamate receptors?
NO and Ketamine
What type of anaesthetic is Ketamine?
A dissociative anaesthetic (member in its own family)
What is the aim of all GA targets?
To decrease neuronal excitability
What do electrophysiology of voltage gated Na+ channel show when GAs are applied?
As the concentration of the drugs increase, the current the current through the Na+ channels gets smaller
What happens to the size of the action potential as GAs are applied?
Size of the action potential decreases
How do GA affect the fusion of vesicles in the presynaptic terminal?
What does this show?
How does this impact the post synaptic site?
Reduced
GA may DIRECTLY interfere with synaptic transmission at the pre synaptic site
Impact at the post synaptic site:
- Less excitation
- Action potentials more spread out
Where are the effects of GA at therapeutic (low) dose?
In the CNS and not the PNS
Where do low concentrations of GAs act?
What does this cause?
- Decrease synaptic transmission in the CNS
- Reticular formation - unconsciousness
- Hippocampus - reduced neuronal activity –> long term amnesia
- Analgesia
- Inhibition of spinal reflexes
What do high concentrations of GAs do?
Loss of:
- Motor control
- Reflexes
- Central control of respiration
- Regulation of the cardiovascular system
What are the stages of anaesthesia?
What happens at each stage?
1) Analgesia
- Reduced responsiveness to painful stimuli
2) Excitation
- Dangerous stage (want to see through as quickly as possible)
- Exaggerated response of reflexes (even though unconscious)
3) Surgical anaesthesia
- Unconsciousness
- Loss of response to painful stimulation
- Loss of exaggerated reflexes
- Short-term amnesia (no memory of the procedure
4) Medullary paralysis
- Desperately try to avoid this stage
- Loss of cardiovascular reflexes and respiratory paralysis -cause death
Why is it difficult to form surgery on obese patients?
Drugs enter the fat and NOT the CNS
What are the advantages of intravenous anaesthetics?
- Easy to administer
- Rapid induction
-
Why is there a rapid induction with intravenous anaesthetics?
- Delivery straight into the blood
- Brain is HIGHLY perfused –> rapidly distributed to the CNS
- Easy to cross the BBB (lipophilic)
- Rapid metabolism –> good induction for anaesthesia, rapid recovery (quick wear off)
What are the disadvantages of intravenous anaesthetics?
- Pain at the site of injection
- Complex pharmacokinetics
- Short duration of action due to redistribution
- ‘Hangover’ effect due to accumulation in the body fat
- Peripheral side effects
What receptors does Ketamine block?
NDMA receptors
What are the positive effects of Ketamine?
- NOT a complete loss of consciousness
- Sensory loss
- Powerful analgesic
- Amnesia
- NO respiratory depression
What are the negative effects of Ketamine?
No use on humans, as:
- Increased inter cranial pressure (hazard)
- Can cause hallucinations, delirium
- Irrational behaviour on recovery
What are the gaseous anaesthetics?
NO, Isoflurane, Desflurane, Sevoflurane
When are gaseous anaesthetics used?
IV?
Gaseous used to MAINTAIN surgical anaesthesia
After originally giving IV until the loss of conciousness
How can the concentration of GA in the blood in the brain?
By altering:
1) The RATE of VENTILATION
2) CONCENTRATION of the drug in the inspired air
When is there a problem with controlling the concentration of GA in the blood in the brain?
When the lungs are diseased or damaged
What are the advantages of the gaseous GA?
1) Can easily change the concentration in the blood and brain (don’t have to wait metabolism)
2) Well tolerated, less side effects
3) Easily cross the alveolar membrane (small lipid soluble molecules)
What do the differences between gaseous A come from?
The solubility of the different agents in the blood and fat
What does the speed of induction and recovery from GA depend upon
Drug solubility and fat
Describe the passage of inhaled drugs around the body?
1) Drug INTO the lungs
2) RAPIDLY equilibriate across the alveolar membrane
3) Blood takes the drug rapidly to the brain and any LEAN tissue (highly perfused)
4) Very quick to equilibriate between the inspired air and the tissues
5) Solubility of the drug in the blood is very low (partitions quickly into the lipids
Do drugs bind well to proteins?
NO
What can be triggered by halogenated GAs?
Malignant hyperthermia:
- Body temperature increase due to rapid contraction of the muscles
- Problems with the heart
