General Anesthesia

Question 1

What is Nitrous Oxide and what does it do?

Answer 1

Inhalational anesthetic
Laughing Gas
Strongly inhibits NMDA receptors

Question 2

What is halothane and what does it do?

Answer 2

Inhalational anesthetic

Potentiates GABA effects at GABA-A receptors

Question 3

What is isoflurane and what does it do?

Answer 3

Inhalational anesthetic

Inhibits output of Thalamocortical neurons

Question 4

What is ketamine and what does it do?

Answer 4

Intravenous anesthetic

Selective inhibitor of NMDA receptors

Question 5

What is pentobarbital/pentobarbitone and what does it do?

Answer 5

Intravenous anesthetic

stereoselectively potentiates GABA

Question 6

What is luciferase?

Answer 6

Luminous protein in fireflies, used for ATP conc assays

Question 7

What is Kainate?

Answer 7

A type of ionotropic glutamate receptor

Question 8

Where are thalamocortical neurons found?

Answer 8

Between the thalamus and the cerebral cortex (convey sensation)

Question 9

What are the structures of inhalational anesthetics?

Answer 9

No clear Structure/Activity relationship
(lots of ethers)
MUST BE GIVEN WITH O2

Question 10

How can you test the potency of anesthetic agents on an animal model?

Answer 10

Tadpole righting reflex loss

Question 11

Anesthetic potency is predicted by what property of the compound?

Answer 11

Solubility in lipid bilayers

Applies mostly to INHALATIONAL anesthetics

Question 12

What is the Lipid theory, name a possible mechanism, and state a problem with this theory

Answer 12

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

Question 13

What is the Lipid theory, name a possible mechanism, and state a problem with this theory

Answer 13

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

Question 14

What are exceptions to the disordering/potency rule?

Answer 14

Long chain alcohols disorder greatly but are weak anesthetics

Question 15

What are the 2 critical observations of the lipid theory?

Answer 15

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)

Question 16

What is stereoselectively potentiated by Pentobarbital? What is the more potent anesthetic?

Answer 16

GABA

(-) isomer

Question 17

True/False? Potency for luciferase inhibition is correlated to potency of general anesthesia

Answer 17

True

Question 18

What is the unitary hypothesis, and what is the specific hypothesis? Which is the leading hypothesis? why?

Answer 18

Unitary:
One molecular target is common to all general anesthetics
Specific:
The targets (maybe proteins?) differ between anesthetics

Question 19

What are the criteria for identifying an anesthetic target site? (5)

Answer 19

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

Question 20

What is the unitary hypothesis, and what is the specific hypothesis? Which is the leading hypothesis? why?

Answer 20

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

Question 21

True/False? Voltage-Gated ion channels tend to be very sensitive to general anesthetics

Answer 21

False

Completely insensitive

Question 22

What are the three basic ionotropic glutamate receptors?

Answer 22

NMDA
AMPA
Kainate

Question 23

What are the three basic ionotropic glutamate receptors?

Answer 23

NMDA
AMPA
Kainate

Question 24

True/False? There are only a few ligand gated ion channels

Answer 24

EXTREMELY false
Many subunits each produced from a single gene
Subunits can combine in different ways to produce receptor subtypes

Question 25

How might GABA A receptors be important for anesthesia?

Answer 25

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

Question 26

How is anesthesia induced by a GABA A receptor agonist (THIP) measured in rats?

Answer 26

Give THIP | measure time until loss of righting reflex

Question 27

General anesthesia and sedation are mediated by what receptors?

Answer 27

GABA-A and its isoforms

Question 28

General anesthesia and sedation are mediated by what receptors?

Answer 28

GABA-A and its isoforms

Question 29

Which GABA A subunit is relevant to explain etomidate's anesthedic effect?

Answer 29

beta 3 subunit

Question 30

What theory suggests a single anesthesia centre? Where is it?

Answer 30

The Mesopontine switch hypothesis | A single anesthesia centre at the junction of midbrain and pons

Question 31

Define the mesopontine switch hypothesis | What are the implications if this theory is true?

Answer 31

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)

Question 32

What are the three arguments for the Mesopontine switch hypothesis?

Answer 32

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

Question 33

Does intraperitoneal injection of Pentobarbital achieve the same anesthetic effect as direct MPTA injections?

Answer 33

Yes

Question 34

What is the hypothesis for multiple distributed anesthetic sites in the brain?

Answer 34

General anesthetics DIRECTLY target multiple areas of the CNS in order to produce their various effects

Question 35

What are the three arguments to support the multiple distributed anesthetic site hypothesis?

Answer 35

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

Question 36

Is the lipid solubility theory correct?

Answer 36

NO