Lecture 23

Question 1

Inhalational anesthetics

Answer 1

Nitrous oxides (N2O), Halothane, Isoflurane

Question 2

Intravenous anesthetics

Answer 2

Ketamine, pentobarbital

Question 3

Properties of General anesthetic

Answer 3

1) Loss of sensation
2) Loss o f consciousness (graded response)
3) Analgesia (loss of sensation and pain without loss of consciousness)
4) Relaxation of skeletal muscles
5) Amnesia

Question 4

First instance to of general anesthesia preventing pain by making patients unconscious

Answer 4

Ether

Question 5

What is laughing gas

Answer 5

Nitrous oxide, induces loss of sensation without becoming unconscious

Question 6

2 types of General Anesthetics

Answer 6

Inhalational and intravenous

Question 7

Requirement of all Inhalational anesthetics

Answer 7

All inhalational anesthetics must be given with oxygen
BUT no clear structure-activity relationship

Question 8

Families of Intravenous anesthetics

Answer 8

Barbiturates, opioids, benzodiazepines, ketamine

Question 9

How is anesthesia measured

Answer 9

Via the loss of the righting reflex

Question 10

What is the Righting reflex

Answer 10

Ability of animals to orient their bodies the right way up

Question 11

First prediction of anesthetic potency

Answer 11

Solubility in bilayers (proved to be false)
Lipophilicity is important for drugs to enter the brain

Question 12

What is MAC

Answer 12

Minimum alveolar concentration
The concentration where 50% of patient no longer respond to pain stimulus

Question 13

What is the Lipid theory

Answer 13

Narcosis starts when any chemically indifferent substance has attained a certain molar concentration in lipids of the cell, concentration depends on nature of animal or cell, but is independent of the narcotic

Question 14

Possible Mechanisms of Lipid therapy by anesthetics

Answer 14

1) Membrane volume expansion in red blood cells (may disrupt ion channels, reversed by pressure in cell)
2) Increase membrane fluidity (making more leaky ion channels, but same at 1degress Celsius body temp)

Question 15

What disproves the Lipid Theory

Answer 15

The cut-off phenomenon and stereoselective anesthetics
It is unlikely that anesthetics target lipids

Question 16

What is the cut off phenomenon

Answer 16

Increase in carbon length for alkanols increases lipid solubility and anesthetic potency
Proved with loss of righting reflex in tadpoles at lower concentrations
EXCEPTION: longest carbon chains have NO anesthetic properties despite being the most lipid soluble

Question 17

What are Stereoselective anesthetics

Answer 17

Where 1 stereoisomer does not have same potency as other, but both stereoisomers have same lipophilicity
Ex. ketamine, shown through different results in righting reflex

Question 18

Stereoselctiveness of Pentobarbital

Answer 18

+PB–>results in depolarization, firing of many action potentials
-PB–>results in hyperpolarization, stronger inhibitory effect, more potent anesthetic

Question 19

Overall action of Pentobarbital (-PB)

Answer 19

Stereoselectively potentiated GABAa (-PB) receptor channel opening–>allowing more chloride to enter cell–>hyperpolarization

Question 20

What is Luciferase

Answer 20

Bioluminescent protein found in fireflies

Question 21

What is the Luciferase Assay

Answer 21

Tests whether a substance can or cannot inhibit purified luciferase
Correlation between potency of general anesthetic and potency to inhibit luciferase

Question 22

What is the correlation between anesthetic and luciferase an indicator of

Answer 22

That anesthetics target proteins to perform their anesthetic effects

Question 23

2 Hypotheses on pattern of anesthetic drugs on proteins

Answer 23

Unitary hypothesis—>only 1 molecular target is common to all general anesthetics (rejected)
Specific hypothesis–>targets differ between anesthetics

Question 24

Metabolic rate and anesthesia

Answer 24

The cerebral metabolic rate is much reduced during anesthesia, the oxygen consumption decreases significantly

Question 25

Potential target for anesthetics

Answer 25

Ion channels
Voltage-gated ion channels–>insensitive to general anesthetics
Ligand-gated ion channels–>have some target receptors for anesthetics (glutamate and GABAa receptor)

Question 26

What are the 3 families of glutamate receptors

Answer 26

NMDA, AMPA, and Kainate

Question 27

Main action of Ketamine

Answer 27

Selectively inhibits NMDA-type glutamate receptors via a use-dependent block

Question 28

Mechanism of Ketamine

Answer 28

1) Ketamine DECREASES the ability of NMDA to activate the NMDA-type glutamate receptor
2) Activating the NMDA-type glutamate receptors with NMDA allowed ketamine to enter the open ion channels and produce STRONGER inhibition
Has selective + used-dependent effect on NMDA receptors

Question 29

Main action of Halothane (gaseous)

Answer 29

Potentiated GABA’s effects at GABAa receptors

Question 30

Requirements for GABAa receptor being a target site for anesthetic drugs

Answer 30

1) The GABAa receptors must be affected t appropriate therapeutic concentration (similar EC50 for general anesthesia and potentiation of GABAa receptors)
2) The GABAa receptor must show appropriate stereoselectivity (-PB, pentobarbital)
3) Agonists of the GABAa receptor must produce anesthesia

Question 31

What is THIP

Answer 31

GABAa receptor agonist
increasing doses of THIP results in faster loss of righting reflex in rats–>produces anesthesia

Question 32

Why GABAa receptors may be important targets for anesthesia

Answer 32

1) most gaseous anesthetics can potentiate GABA at surgical concentrations
2) Pentobarbital (stereoselective, -PB) can potentiate GABA
3) Ketamine and N2O do NOT potentiate GABA

Question 33

Which receptor targets are important for anesthesia

Answer 33

Glutamate and GABAa receptors

Question 34

Main action of Etomidate

Answer 34

Potentiates function of Beta2 and Beta3 subunits of GABAa receptors

Question 35

Outcome of mutated B3 subunit of GABAa receptor in mice

Answer 35

Mice with point mutation of Beta3 subunit PREVENTS etomidate (and propofol) from potentiating the GABA response in Beta-3 containing receptors

Question 36

What does Beta2 subunits of GABAa receptor induce

Answer 36

Sedation by etomidate within GABAa receptors with Beta2 subunit
Less sedated–>less locomotion

Question 37

2 hypotheses where general anesthetics work in the brain

Answer 37

1) Work in anesthesia center (MPTA) (Mesopontine Switch Hypothesis)
2) Anesthetics have multiple direct action in different brain regions

Question 38

Evidence that supports the Mesopontine Switch Hypothesis (MPTA)

Answer 38

1) Mapping entire rat brain with pentobarbital injections found hotspots
2) Small doses injected directly into these hotspots (MPTA) have rapid anesthetic effects
3) Lesions to the MPTA decrease anesthetic effects (lesioned group required more pentobarbital to achieve anesthesia)

Question 39

MPTA and GABAa receptors

Answer 39

MPTA is NOT important for anesthetic drugs that do NOT target GABAa receptors

Question 40

Drugs affected by MPTA lesions

Answer 40

Shift dose-response curve to right for GABAergic drugs (etomidate, propofol)
No effect on ketamine

Question 41

Final say of Mesopontine switch hypothesis

Answer 41

May apply to GABAergic drugs but it does NOT apply to all anesthetic drugs (ketamine)

Question 42

Evidence that supports the Multiple, distributed, anesthetic sites in the brain hypothesis

Answer 42

1) General anesthetics distribute throughout the CNS
2) Target receptors (NMDA, GABAa) are widespread throughout the CNS
3) Different components of anesthesia are dependent on far-flung regions of the CNS (suppress movement and pain in spinal cord, impair memory and consciousness in the hippocampus and cerebral cortex)

Question 43

Main action of Isoflurane

Answer 43

Inhibit the output of thalamocortical neurons to interrupt the signaling of pain to the brain (little response to mechanical stimulation