General Anesthesia Flashcards
What is Nitrous Oxide and what does it do?
Inhalational anesthetic
Laughing Gas
Strongly inhibits NMDA receptors
What is halothane and what does it do?
Inhalational anesthetic
Potentiates GABA effects at GABA-A receptors
What is isoflurane and what does it do?
Inhalational anesthetic
Inhibits output of Thalamocortical neurons
What is ketamine and what does it do?
Intravenous anesthetic
Selective inhibitor of NMDA receptors
What is pentobarbital/pentobarbitone and what does it do?
Intravenous anesthetic
stereoselectively potentiates GABA
What is luciferase?
Luminous protein in fireflies, used for ATP conc assays
What is Kainate?
A type of ionotropic glutamate receptor
Where are thalamocortical neurons found?
Between the thalamus and the cerebral cortex (convey sensation)
What are the structures of inhalational anesthetics?
No clear Structure/Activity relationship
(lots of ethers)
MUST BE GIVEN WITH O2
How can you test the potency of anesthetic agents on an animal model?
Tadpole righting reflex loss
Anesthetic potency is predicted by what property of the compound?
Solubility in lipid bilayers
Applies mostly to INHALATIONAL anesthetics
What is the Lipid theory, name a possible mechanism, and state a problem with this theory
Membrane volume expansion shown to occur in RBCs (disrupts ion channels?) AND pressure reverses anesthesia
Increased membrane fluidity
shown to occur BUT mimicked by 1 degree rise AND correlation breaks down
What is the Lipid theory, name a possible mechanism, and state a problem with this theory
Membrane volume expansion shown to occur in RBCs (disrupts ion channels?) AND pressure reverses anesthesia
Increased membrane fluidity
shown to occur BUT mimicked by 1 degree rise AND correlation breaks down
What are exceptions to the disordering/potency rule?
Long chain alcohols disorder greatly but are weak anesthetics
What are the 2 critical observations of the lipid theory?
Cut-off phenomenon: increasing carbon length increasing lipid solubility increasing anesthetic potency UNTIL cut off is reached
Stereoselective anesthetics:
IV ketamine in rats (+ isomer more potent, not explained by any difference in brain penetration)
Pentobarbital (- is more potent anesthetic)
What is stereoselectively potentiated by Pentobarbital? What is the more potent anesthetic?
GABA
(-) isomer
True/False? Potency for luciferase inhibition is correlated to potency of general anesthesia
True
What is the unitary hypothesis, and what is the specific hypothesis? Which is the leading hypothesis? why?
Unitary:
One molecular target is common to all general anesthetics
Specific:
The targets (maybe proteins?) differ between anesthetics
What are the criteria for identifying an anesthetic target site? (5)
Must be affected at appropriate (therapeutic) concnetration
Must show (any) appropriate stereoselectivity
Agonists (or antagonists) must produce anesthesia
“Knockout” animals should not be susceptible to anesthetic
Transgenic animals should be more/less susceptible
What is the unitary hypothesis, and what is the specific hypothesis? Which is the leading hypothesis? why?
Unitary:
One molecular target is common to all general anesthetics
Specific:
The targets (maybe proteins?) differ between anesthetics
Specific Hypothesis
1) Ketamine acts selectively on NMDA receptors
2) Not all IV anesthetics inhibit NMDA receptors
N2O is an inhalational anesthetic that DOES strongly inhibit NMDA receptors
True/False? Voltage-Gated ion channels tend to be very sensitive to general anesthetics
False
Completely insensitive
What are the three basic ionotropic glutamate receptors?
NMDA
AMPA
Kainate
What are the three basic ionotropic glutamate receptors?
NMDA
AMPA
Kainate
True/False? There are only a few ligand gated ion channels
EXTREMELY false
Many subunits each produced from a single gene
Subunits can combine in different ways to produce receptor subtypes
How might GABA A receptors be important for anesthesia?
1) Most gaseous anesthetics can potentiate GABA at surgical concentrations
2) The well-known GABA-potentiating effect of pentobarbital
3) Ketamine and N2O do not potentiate GABA
How is anesthesia induced by a GABA A receptor agonist (THIP) measured in rats?
Give THIP
measure time until loss of righting reflex
General anesthesia and sedation are mediated by what receptors?
GABA-A and its isoforms
General anesthesia and sedation are mediated by what receptors?
GABA-A and its isoforms
Which GABA A subunit is relevant to explain etomidate’s anesthedic effect?
beta 3 subunit
What theory suggests a single anesthesia centre? Where is it?
The Mesopontine switch hypothesis
A single anesthesia centre at the junction of midbrain and pons
Define the mesopontine switch hypothesis
What are the implications if this theory is true?
General (read: GABAnergic) anesthetics produce their effects by targeting a small brain stemp area called the Mesopontine tegmental anesthesia area (MPTA)
If true, it suggests the possibility of more selective drugs that might avoid respiratory depression (and other common side effects of GAs)
What are the three arguments for the Mesopontine switch hypothesis?
1) Brain mapping with pentobarbital injections - MPTA was anesthetic “hotspot”
2) Extremely low doses of pentobarbital at MPTA were enough to cause sedation
3) Rats with MPTA lesions needed more pentobarbital to receive anesthesia
Does intraperitoneal injection of Pentobarbital achieve the same anesthetic effect as direct MPTA injections?
Yes
What is the hypothesis for multiple distributed anesthetic sites in the brain?
General anesthetics DIRECTLY target multiple areas of the CNS in order to produce their various effects
What are the three arguments to support the multiple distributed anesthetic site hypothesis?
1) GAs distribute throughout the CNS
2) Target receptors (eg NDMA, GABA A) are widespread in the brain
3) DIfferent components of anesthesia are dependent on far-flung regions of the CNS*
- Suppression of movement and pain - Spinal cord
- Impaired memory and consciousness - hippocampus/cerebral cortex
Is the lipid solubility theory correct?
NO
