Principles of GA (09.03.2020) Flashcards
What would you want from a GA?
- Loss of consciousness
- Suppression of reflex responses
- Relief of pain (analgesia)
- Muscle relaxation
- Amnesia
What are the 2 properties that all GAs have?
- loss of conciousness at low concentration
- suppression of reflex responses at high concentrations
What are the 2 main groups of GAs?
- gaseous/inhalation agents
- i.v. agents
Gaseous GAs
- nitrous oxide
- diethyl Esther
- halothane
- enflurane
Intravenous GAs
propofol
etomidate
Meyer/Overton Correlation
- The more lipid soluble a GA, the more potent.
- Anaesthetic potency increases in direct proportion with oil/water partition coefficient
- not similar structurally
Nitrous oxide MoA
- blocks NMDA type glutamate receptors
- probably compete with co-agnost glycine
=> Blocks an excitatory receptor
GAs – Mechanism of action: Neuroanatomy
LOSS OF CONCIOUSNESS
- Depress excitability of
thalamocortical neurons - Influences reticular
activating neurons
If you…. you can convince the brain that it is time to sleep.
Suppression of reflex responses
- GABA and glycine are responsible for sending pain signal from spine to brain
- you are trying to disconnect the spine from he spinal cord in transmitting painful stimuli
Amnesia
↓ synaptic transmission in
hippocampus/amygdala
alpha 5 GABAR in that region
contribute to amnestic effetct
Use of GAs in a clinical setting
- induce with i.v. for fast induction
- control the level and depth of anaesthesia with an inhalation agent (this is what gives you the control over anaesthesia)
Clinically you use anaesthetics for loss of consciousness and suppression of reflex responses.
For the other effects you would give other drugsL
- analgesia -> opioid (e.g. fentanyl)
- Muscle relaxation -> neuromuscular blocking drugs, e.g. suxamethonium
- amnesia -> benzodiazepine (e.g. midazolam) also helps relax pre-op
What are the problems with the Meyer-Overton Correlation?
Problems:
- At relevant anaesthetic concentrations, change in bilayer was minute
- How would this change impact membrane proteins?
If the MoA were to influence membranes there is not much supporting this.
Lipid solubility wouldn’t cause any of the effects
GABAA receptor as a target
- GAs increase the activity of GABA neurones (inhibitory)
- (inhalation agents are 50% less effective than intravenous agents)
- Receptor composition is relevant
- beta-3: suppression of reflex responses
- alpha-5: amnesia
(=> altered synaptic function)
Glycine as a target
- targeted by some inhalational agents
- alpha-1 subunits is important for suppression of reflex responses
- imcreased inhibitory activity
(=> altered synaptic activity)
NMDA type glutamate R as a target
- blocks excitatory R
- competes with glycine
- Assumed to mediate the anaesthetic induced effects on consciousness and mobility
(=> altered synaptic function)
Neuronal nicotinic AChR as a target
- linked to analgesic effect
- Volatile anaesthetic inhibit neuronal nicotinic Ach receptors and this contributes to the analgesic effects of these anaesthetics
- Intravenous drugs can act on these targets but only at concentrations above that required for anaesthesia
- Ach receptors do not seem to contribute to the hypnotic effects.
- GAs inhibit the receptors
- decrease in stimulatory firing
(=> altered synaptic function)
TREK as a target
- background leak potassium channels
- mediate hyper polarisation of neurones (K+ leaks out)
- increase K+ efflux and length of hyper polarisation
- > decreased neuronal excitability
- strongly linked to consciousness
(=> reduced neuronal excitability)
Neuroanatomical site for loss of consciousness
- GA Depress excitability of thalamocortical neurons (GABAA Receptor rich cortical neurones and reticular activating neurones)
- GA Influences reticular activating neurons (there are TREK channels that GAs hyper polarise, so GAs can convince the brain that it is time to sleep).
The RAS recognises when there are many inputs coming in. If there aren’t many then it gives the signal that you can go to sleep. GAs convince the brain that it is time to sleep.
Neuroanatomical site for loss of reflex responses
- suppression of reflex pathways in the spinal cord
- GABA and glycine are important in relaying pain information to the brain
- ‘disconnect brain from spinal cord in receiving painful stimuli’
neuroanatomical site for amnesia
- ↓ synaptic transmission in hippocampus/amygdala
- massively impairs memory
- alpha 5 subunit of GABA R contribute to the amnestic effect, many of those found in that region of the brain.
Molecular targets of i.v. GAs
- GABA A R
- Glycine R
-> strong effects on those two, not too much on other targets
Molecular targets of inhalation GAs
- GABA A
- GABA R
- also more diffuse effects on other targets
- less specific effects
intravenous vs. inhalational GAs clinically
Inhalation Intravenous
- Rapidly eliminated - Fast Induction (straight into blood)
- Rapid control of the - Less coughing/
depth of anaesthesia excitatory phenomena
Coughing due to GAs
Airway irritation can lead to the cough reflex being initiated -> inhalational anaesthetics.
How do inhalational agents get to the brain?
- readily cross the alveoli
- quick exchange between alveoli, blood and Britin
=> control over depth of anaesthesia
Blood-gas coefficient
low bg partition coefficient
- > it does not dissolve well in the blood (remains gaseous)
- > efficient transfer to the brain
- > e.g. inhalaational GAs -> quick, fast in
High blood:gas coeffeicient:
- If it dissolves in the blood, it is almost trapped there and you don’t get that much across into the brain.
Ideally you want a GA with a low blood:gas partition coefficient to have fast induction and rapid elimination.
Why are anaesthetics dangerous?
- giving patients many drugs at the same time during surgery
- putting the patient in a quite dangerous state.
