W7: General Anaesthetics Flashcards
What is the triad of general anaesthesia?
Need for unconsciousness
Need for analgesia
Need for muscle relaxation (loss of motor reflexes)
How do general anaesthetics work generally?
Work by depressing CNS activity
What is the structure of inhalational anaesthetics?
Simple unreactive compounds
Short chain molecules
No one chemical class
The lipid theory: he adds a certain amount of GA to a bowl of tadpoles. What is the relationship between concentration or agents and lipid:water partition coefficient?
Concentration of agents required to immobilise tadpoles is inversely proportional to its lipid:water partition coefficient.
What is the olive oil (lipid) : water partition coefficient?
How much the individual agent would rather dissolve into olive oil or go into water. Partitions in these two compartments. Measure of lipid solubility.
Hydrophobicity/lipid solubility is important for anaesthetic action. What does this indicate?
Indicates that a GA agent needs to get into cells via the cell membrane. Neurones have a lot of lipid in their myelin sheath, so GA could target this in the brain.
What are some subsequent observations of the lipid theory?
- when concentration of anaesthetic in the cell membrane is 0.05mM, you get general anaesthesia, true for any agent
- anaesthesia occurs when the volume of lipid expanded by 0.4%
- high (atmospheric) pressure reverses the anaesthesia (by squeezing cells to reverse cell expansion)
- theory points to interference of conduction of nerve impulses
What is the protein theory?
Perhaps lipid solubility is merely required for access to proteins (ion channels, receptors)
What is the ‘cut-off’ phenomenon anaesthetic potency - for homologous series of long-chain anaesthetic compounds?
As chain length increases, lipid solubility increases.
But potency stops beyond a certain length so will no longer act as a GA
Stereo-selectivity of anaesthetic potency is preserves with protein binding. What does this mean?
Isomers of the same molecule have the same lipid solubility but different anaesthetic potency. So to do with binding.
What does the protein theory suggest?
So evidence points to GAs mediating effects by binding to hydrophobic pockets on proteins, with pockets being within the membrane, so lipid solubility is important for access. There is no specific protein which all GAs bind to to produce general anaesthesia.
What are the 2 major ion channels hit by general anaesthetics?
GABA’A receptors
K+ ion channels
What happens when GA agents bind to GABA’A receptors?
It activates the receptor more, making GABA’A activation bigger (which is an inhibitory neurotransmitter), so inhibition effects are increased in the brain = CNS depressant effects.
What happens when GA agents bind to K+ channels?
Activates K+ channels, increasing hyperpolarisation, thus decreasing membrane excitability, which is a CNS depressant effect.
What other ion channels can be affected by GA agents (but are not always affected)?
Agents tend to inhibit excitatory ligand-gated channels, e.g., NMDA receptor (glutamate), 5-HT3, ACh nicotinic receptor
Agents activate inhibitory ligand-gated channels e.g., glycine
What are the major effects on the CNS through inhibition of synaptic transmission?
Decreased neurotransmitter released
Decreased post-synaptic responsiveness
What effects can be produced due to the depression of CNS activity?
- unconsciousness (likely) mediated by action at reticular formation in the midbrain
- analgesia, action at the thalamus
- loss of reflexes due to effects on the spinal cord
What is the order of things lost in the presence of increasing GA?
Initially in the absence of GA, people can form memories, first thing inhibited by GA.
Then loss of consciousness and analgesia
Then movement is suppressed - inhibition of motor reflexes
When can GA be performed?
On the bottom part of the movement curve, since all of the responders meet the GA criteria.
What happens if you keep increasing GA concentration past the level of no movement?
You start to inhibit the cardiovascular respiratory system, meaning they are dead and have been overdosed. Thus there is a very narrow therapeutic window.
